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The Signaling of Cellular Senescence in Diabetic Nephropathy

Yabing Xiong, Lili Zhou

Oxidative Medicine and Cellular Longevity · 2019 · Review

doi:10.1155/2019/7495629

Abstract

Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) in western countries. Notably, it has a rapidly rising prevalence in China. The patients, commonly complicated with cardiovascular diseases and neurologic disorders, are at high risk to progress into end-stage renal disease (ESRD) and death. However, the pathogenic mechanisms of diabetic nephropathy have not been determined. Cellular senescence, which recently has gained broad attention, is thought to be an important player in the onset and development of diabetic nephropathy. In this issue, we generally review the mechanisms of cellular senescence in diabetic nephropathy, which involve telomere attrition, DNA damage, epigenetic alterations, mitochondrial dysfunction, loss of Klotho, Wnt/ β -catenin signaling activation, persistent inflammation, and accumulation of uremic toxins. Moreover, we highlight the potential therapeutic targets of cellular senescence in diabetic nephropathy and provide important clues for clinical strategies.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 22, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1Diabetic nephropathy (DN) has been the leading cause of CKD and renal failure in developed countries. In the past two decades, the morbidity and mortality of DN have been rising rapidly in the worldwide population. Along with the kidney injury, diabetic patients often suffer from multiple complications, such as retinopathy, neuropathy, and cardiovascular diseases. All of them contribute to a high risk of death. Besides health problems in patients, DN also leads to a heavy burden to the society.

2Previous reports indicate that the mechanisms of DN involve a multifactorial interaction of metabolic and hemodynamic factors such as high blood glucose, advanced glycation end-products (AGEs), and the renin-angiotensin system (RAS). They further link to the activation of protein kinase C- (PKC-) induced generation of reactive oxygen species (ROS), which further mediates the activation of downstream transcription factor nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB). Thus, the main treatments of DN refer to modulate glycemic and blood pressure through insulin and RAS inhibitors. However, they could only delay the progression of DN but not prevent or cure it. Patients suffering from DN still inevitably reach the stage of ESRD at an alarming rate in both developed and developing countries. Hence, the new pathogenic mechanisms except hyperglycemia and hypertension should be determined for a better management of DN. Recently, the emerging role of cellular senescence in DN has attracted a broad attention. However, a comprehensive elucidation has not yet been achieved. In the present review, we will focus on the role of cellular senescence and its related mechanisms in DN. Furthermore, we will explore the potential therapeutic targets of cellular senescence and provide important clues for clinical strategies in the management of DN.

2. DN and Renal Aging

3The aging kidneys undergo a wide range of macrostructural changes, such as decreased cortical volume, increased surface roughness, and augmented numbers and sizes of cysts, which correspond to the typical microstructural features of glomerulosclerosis, tubular atrophy, interstitial fibrosis, and nephron loss. Cellular aging or cellular senescence is the critical factor for the process of aging. Although the senescent cells remain viable, they show typical changes with enlarged and flattened cell bodies, apoptosis resistance, increased activity of senescence-associated β-galactosidase (SA-β-gal), and upregulation of cyclin-dependent kinase (CDK) inhibitors including p16INK4A, ARF proteins, and p21. Furthermore, senescent cells, with the secretory features known as the senescence-associated secretory phenotype (SASP), could produce proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and monocyte chemoattractant protein1 (MCP-1), to greatly affect the neighboring cells.

4Recent reports show that CKD presents as a clinical model of premature aging. Wang et al. introduced a new concept of CKD-associated secretory phenotype (CASP), which indicates that senescent renal cells could secrete SASP components of various cytokines such as IL-1, IL-6, and TNF-α. Other reports also show that DN is highly associated with accelerated aging in various types of cells such as tubular cells, podocytes, mesangial cells, and endothelial cells. Notably, hyperglycemia could directly induce cellular senescence in mesangial and tubular cells. Interestingly, high glucose could also induce macrophages to secrete SASP components, thus promoting the development of a low-grade inflammatory state and cellular senescence.

5Besides hyperglycemia, the production of AGEs and induction of oxidative stress, chronic persistent inflammation, glucose toxicity, and lipid metabolism disorder under DN disease conditions could cooperatively promote the growing microenvironment for senescent cells. Conversely, senescent cells could accelerate the progression of disease. The studies show a strong association between glomerular expression of p16INK4A and proteinuria. In addition, the excessive SA-β-gal activity and expression of p16INK4A in tubules are positively correlated with interstitial fibrosis, tubular cell atrophy lesions. Of note, tubular cell senescence is intimately associated with BMI and blood glucose level, implicating that controlling cellular senescence plays a critical role in the therapeutics of DN.

6There are two main consequences from the accumulation of senescent cells. First, as one might expect, because of permanent cell cycle arrest, cellular senescence may cause a loss of self-repair capacity and regenerative ability. These would lead to the exhaustion of renal cells as well as other progenitor or stem cells. A study shows that the number of endothelial progenitor cells is 30%–50% lower in patients with chronic kidney disease than that in healthy subjects. There are a limited reservoir, decreased population, and low renewal efficiency of stem cells in DN-affected kidneys, which would certainly accelerate the progression of disease. Second, senescent cells could produce proinflammatory and matrix-synthesizing cytokines, such as IL-6 and TGF-β. These SASP-associated molecules may cause persistent inflammation and fibrosis, as well as stem and renal cell renewal dysfunction in a paracrine and autocrine fashion. Collectively, cellular senescence participates in many pathological processes to accelerate the progression of DN. In this review, we discuss the role of cellular senescence in the pathogenesis of DN, highlight new findings on the mechanisms of cellular senescence (Figure 1), and propose the novel strategies to treat patients with DN by targeting cellular senescence.

3.1. Telomere Attrition and Cellular Senescence

7Telomeres are stretches of repetitive DNA, which are located at the end of each chromosome. Telomeres protect the chromosomes from degradation or fusion. In repeated cell division, the length of a telomere may gradually shorten due to the lack of telomerase activity, an enzyme that helps to maintain the length of the chromosome.

8Telomere shortening could occur in both type 1 and type 2 diabetes. It can be accelerated by inflammation, hyperglycemia, AGEs, and chronic oxidative stress, the main mechanisms of diabetes. Telomere attrition could trigger stress-induced premature senescence (SIPS). As early as 1999, it was found that telomere shortening is displayed in kidney diseases. Consistently, recent studies show that high glucose induces accelerated senescence in proximal tubular cells, which is related to telomere shortening. In both type 1 and type 2 diabetes, chromosomal telomere attrition is associated with renal cell senescence, proteinuria, and the progression of DN. After the prevention of telomere attrition, fenofibrate provides beneficial effects on the treatment of DN. The p53-p21-Rb signaling pathway is involved in the cellular senescence caused by telomere attrition under the condition of high glucose. Besides the kidney parenchymal cells, the telomere of white blood cells in DN patients also displays the state of shortening. Although suggested as a biomarker in coronary heart disease, telomere shortening could also be applied in the diagnosis of DN. Supporting findings show that there is a high association between telomere length shortening and the progression of nephropathy through the mass population surveys.

3.2. DNA Damage and Cellular Senescence

9DNA damage has been thought to be a main cause of cellular senescence since the late 1950s. Besides the “wear and tear damage” during normal aging, there are various stress factors that could directly induce the damage of DNA, such as oxidative stress, ultraviolet (UV) or gamma irradiation, chemotherapeutics, and hyperproliferation caused by the Ras oncogene. Under diabetic conditions, hyperglycemia-induced generation of ROS and accumulation of AGEs may induce DNA damage and then trigger premature senescence in cells. In type 1 diabetes rat models, AGEs and oxidative stress could induce DNA damage in both glomerular and tubular cells.

10All of these DNA-damaged stressors could trigger a permanent DNA damage response (DDR) that leads to the activation of phosphatidylinositol 3 kinase-like kinases, such as ataxia telangiectasia-mutated (ATM) or ataxia telangiectasia-mutated and Rad3-related (ATR) kinases. These kinases subsequently activate P53 and its transcriptional target p21CIP1/WAF1. In turn, p21CIP1/WAF1 inhibits cyclin-dependent kinase 2- (CDK2-) mediated phosphorylation of the retinoblastoma protein (Rb). The hypophosphorylated Rb binds to the E2F transcription factor, preventing E2F through interacting with the transcription machinery. This process ultimately results in permanent cell cycle arrest, i.e., cellular senescence. This pathway is also called ATM/ATR-p21axis. Ultimately, senescent cells exhibit elevated levels of DNA damage response proteins 53BP1 and γH2AX and poor repair capacity for DNA strands. These could induce the restructure of the epigenome (see below), such as CpG methylation patterns.

3.3. Epigenetic Alterations and Cellular Senescence

11Epigenetics refers to heritable alterations in gene expression and phenotype without involving changes in the DNA sequence. Epigenetic modifications include cytosine methylation of DNA (DNA methylation, DNAme), histone posttranslational modifications (PTMs), and noncoding RNAs. Alterations in the epigenome underlie the dynamic switching of chromatin between a transcriptionally silent compact structure (heterochromatin) and an active relaxed structure (euchromatin) that cooperatively regulate gene expression.

12DNAme occurs primarily, but not exclusively, at the sites of cytosine-guanine (CpG) dinucleotides. DNAme usually represses gene transcription through recruiting repressor complexes or precluding transcription factors. However, the regulatory effects of DNAme can vary from gene repression to gene activation, which largely depends on the genomic contexts of the targeted sequences, such as promoters, gene bodies, enhancers, and repeated sequences. PTMs mainly include histone lysine acetylation (HKAc) and histone lysine methylation (HKme). HKAc activates gene expression, while HKme activates or represses transcription depending on the lysine residue modified and the extent of methylation (mono-, di-, or trimethylation). Other histone modifications consist of phosphorylation, sumoylation, ubiquitination, ADP-ribosylation, and O-GlcNAcylation. They are also important but not well-studied.

13Epigenetic changes could appear in the very early stage of DN. In 5-week-old db/db mice, the expression of Agt, an important component of the renin-angiotensin system, is upregulated by histone H3K9 acetylation. Similarly, the hypomethylation of CpG islands in Claudin-1 gene is also found at a very early stage in diabetes before the increase in albuminuria.

14Increasingly, epigenetic changes are thought to be important in the development of DN through the induction of oxidative stress. In a rat model of diabetes, H3K27me at the enhancer site of zeste 2 repressive complex 2 subunit (EZH2) dampens the expression of the endogenous antioxidant inhibitor thioredoxin-interacting protein (TXNIP) via repressing the transcription factor PAX6. The inhibition of EZH2 augments proteinuria, podocytopathy, and renal oxidative stress, through the inhibition of glomerular TXNIP expression. In addition, high glucose-mediated TXNIP expression is coordinated by histone acetylation and methylation in diabetic kidneys. Similarly, in podocytes, high glucose could induce CpG promoter hypomethylation and histone H3 hyperacetylation through the activation of histone GCN5 acetyltransferase, which would drive the expression of p66Shc, the key regulator of oxidative stress and player in lifespan shortening. Furthermore, high glucose could also recruit Suv420H2 methyltransferase and LSD1 histone dimethyltransferase to the gene promoter of superoxide dismutase 2 (SOD2), resulting in the downregulation of SOD2, a strong endogenous antioxidant.

15Epigenetic alterations also play important roles in persistent inflammation and autophagy deficiency, two main mechanisms of cellular senescence. In vascular endothelial cells and inflammatory cells, high glucose induces H3K4me1 activation through SET7 lysine methyltransferase to encode the proinflammatory factor NF-κB. More and more studies show the important roles of noncoding RNAs in the development of DN. In db/db mice, miRNA-125b represses H3k9me3 through the downregulation of Suv39h1 histone methyltransferase, which leads to the upregulation of MCP-1 and IL-6, the two chemoattractants for the differentiation and migration of monocytes and lymphocytes. Another noncoding RNA named miRNA-146a, a well-known anti-inflammatory microRNA, increases in the early stage of DN to protect against inflammation and renal fibrosis through inhibiting the activation of M1 macrophage. Additionally, high glucose induces the activation of histone deacetyltransferase 4 (HDAC4) in podocytes, which leads to the deacetylation and silence of STAT1, a named gene in promoting autophagy to exert renoprotective function. Furthermore, the administration of histone deacetylase (HDAC) inhibitor trichostatin A reduces kidney injury through alleviating the loss of Klotho, a well-known antiaging protein. These studies further confirm the mediating role of epigenetic alterations in cellular senescence.

3.4.1. Mitochondrial Reactive Oxygen Species (mtROS) and Mitochondrial Dysfunction

16ROS can be both a trigger and an effector in the aging process and have been viewed as a cause of the aging process since 1996. Mitochondrial ROS (mtROS) could be driven by external stimuli, such as inflammatory cytokines, growth factors, or environmental toxins. The overproduction of mtROS increases in natural aging and age-related diseases. The production of mtROS originates from the defects in the electron transport chain (ETC), which promotes electron leakage to form superoxide radicals, a key player in cellular senescence and accelerating aging. The overproduced mtROS could damage protein, lipid, and DNA, which further trigger the pathological changes. It is noteworthy that in diabetic nephropathy, the altered metabolic state requires extra demands of ATP, which would accelerate electron leakage to produce excessive ROS. The accumulative ROS in the mitochondrion has a detrimental effect in the integrity and content of mitochondrial DNA (mtDNA), which encodes the subunits of ETC complexes. This would further induce mitochondrial dysfunction and increase the production of ROS. Notably, 30% of diabetic patients are suffering from mitochondrial dysfunction as well as reduced mitochondrial biogenesis, which is tightly associated with the severity of kidney diseases.

17However, the exact role of ROS in cellular senescence is controversial. Although ROS is commonly considered as a cause of cellular senescence, recent findings show that it also extends Drosophila's lifespan, especially through respiratory complex I reverse electron transport. Other reports also show that low levels of ROS could serve as second messengers to extent lifespan in Caenorhabditis elegans. Moreover, chemical inhibition of glycolysis or exposure to metabolic poisons that block respiratory complex I (rotenone, paraquat, or piericidin A) or complex III (e.g., antimycin A) also prolong lifespan in C. elegans in a ROS-dependent manner. Thus, the role of ROS homeostasis in cell aging under diabetic conditions may need more studies to confirm.

18It is noteworthy that the production of mtROS could induce the mutations of mtDNA, which contributes to the aging process. This theory is confirmed by mitochondrial mutator mice, an early aging mice model expressing a proofreading-deficient DNA polymerase POLGγ. In those mice, the accumulated mutations of mtDNA significantly accelerate aging phenotype. Recently, the evidences of mtDNA mutation are shown in DN patients. A study shows that mtDNA mutation G13997A in ND6 gene, a key gene encoding one of the subunits of respiration complex I (NADH dehydrogenase), positively correlates with the development of diabetes and related nephropathy. However, some studies show that mutations of mtDNA are not major contributors to aging, especially in fruit flies. The reason lies in that fruit flies are less sensitive to mtDNA mutations in adulthood than during development. Hence, more studies are needed to prove the correlation between mtDNA mutations and cellular senescence in renal cells.

3.4.2. Mitophagy Impairment and Early Senescence

19Mitophagy plays an important role in preserving healthy mitochondria via the removal of altered mitochondria, clearance of protein aggregates. Mitophagy exerts protective functions in inhibiting apoptosis, reducing ROS production, and anti-inflammation. It is reported under diabetic condition, more than 50% of renal tubular cells exhibit fragmented mitochondria, concomitant with the significant upregulation of mtROS in the renal cortex. These suggest the loss of mitophagy in DN.

20Mitophagy depends on the signaling cascade of kinases. The most important kinase is the PTEN-induced putative kinase 1 (PINK1). Upon damage, PINK1 transduces signals to the cytosolic E3 ubiquitin ligase Parkin. Parkin then amplifies the signals of mitophagy by facilitating PINK1-mediated recruitment of optineurin (OPTN) and NDP52. Optineurin (OPTN) contains an ubiquitin-binding domain with the ability of binding polyubiquitinated cargo and transporting cargo to form autophagosomes. The loss of expression in Parkin correlates with lifespan shortening, while the overexpression of Parkin extends longevity. Similarly, the knockdown of PINK1 shortens lifespan and accelerates aging. Interestingly, recent report shows that OPTN is involved in high glucose-induced senescence in renal tubular epithelial cells.

21A large body of studies show that mitophagy is defective in diabetic kidneys, concomitant with mitochondrial abnormalities, overproduced mitochondrial ROS, and reduced expression of PINK and Parkin. Indeed, podocytes show a high rate of baseline autophagy with aging. However, under diabetic status in vivo and high glucose conditions in vitro, the high basal level of autophagy in podocytes is flawed, which facilitates cell injury, glomerular damage, and the progression of kidney diseases. Hence, it can be presumed that in a diabetic setting, defects in mitophagy could induce early senescence in different renal cells and further promote the progression of kidney diseases.

3.5. Falling Levels of Klotho and Dysfunction of the Klotho-FGF-23 Axis

22Klotho is an antiaging protein and is predominantly expressed in normal tubular cells. Klotho could act on multiple signals such as insulin and Wnts and exerts important protection in kidney function. The decline of Klotho could be seen in an early stage of kidney diseases, and this deficiency is linked to accelerated aging, cellular senescence, vascular calcification, and oxidative stress. However, the underlying mechanisms remain poorly understood. Some reports show Klotho protects against cellular senescence through activating the forkhead transcription factor FOXO, a negative regulator of mtROS generation. Furthermore, Klotho also has endogenous anti-inflammatory effects and antifibrotic properties. Klotho also plays a role in mineral metabolism disorders, which would further affect renal aging. Klotho promotes calcium absorption and phosphate excretion in kidneys and serves as a permissive coreceptor of fibroblast growth factor 23 (FGF-23), the hormone regulating phosphate and vitamin D. This is called the Klotho-FGF-23 axis. The loss of Klotho promotes hyperphosphatemia, a risk factor of senescence process and longevity.

23Diminished expression of Klotho is a common feature of DN and is observed at the earliest stage of the disease. The loss of Klotho could be associated with multiple mechanisms such as hypermethylation of Klotho gene, NF-κB-induced falling level of Klotho gene. Recent studies show that increasing activity of integrin-linked kinase protein (ILK) reduces Klotho gene expression, which leads to cellular senescence in renal cells. Large amounts of studies show that the loss of Klotho links to lifespan shortening, skin and muscle atrophy, osteoporosis, and calcification. Under uremia condition, Klotho retards epithelial cell senescence through decreasing oxidative stress, NF-κB activity, etc.. A survey in humans further confirms that the serum level of Klotho declines with age, and Klotho gene displays single nucleotide polymorphism which correlates with reduced longevity and the pathophysiology of age-related disorders.

3.6. Wnt/β-Catenin and Cellular Senescence

24Despite being relatively silent in normal adult kidneys, Wnt/β-catenin signaling is reactivated in a wide range of chronic kidney diseases (CKD), such as diabetic nephropathy, obstructive nephropathy, adriamycin nephropathy (ADR), polycystic kidney disease, and chronic allograft nephropathy. The canonical Wnt/β-catenin signaling involves β-catenin dephosphorylation in serine/threonine residues, which leads to its translocation to the nucleus, where it binds to transcription factor T-cell factor (TCF)/lymphoid-enhancer binding factor (LEF) to induce the expression of downstream target genes. However, in diabetic status, the accumulated intracellular ROS might divert the limited pool of β-catenin from TCF/LEF to forkhead box O- (FOXO-) mediated transcription that leads to insulin deregulation. Notably, the latter plays a pivotal role in the aging process.

25Recent evidence suggests that the renin-angiotensin-aldosterone system (RAS) is mediated by Wnt/β-catenin signaling. Zhou et al. reported that the promoter regions of all RAS genes contain putative TCF/LEF-binding sites, and β-catenin induces the binding of LEF-1 to these sites in renal tubular cells. Ectopic β-catenin causes the upregulation of all RAS genes. Notably, RAS activation contributes to renal aging through various mechanisms. Several studies discover that angiotensin II, a key substance of RAS, can induce senescence in renal cells and lead to the development and progression of age-related diseases. Ang II induces premature senescence via both STAT3/mTOR-regulated autophagy and the p53/p21 pathway, which further drives fibrosis and redox state. Notably, ROS can also induce the expression of p16INK4A, a trigger in cell cycle arrest and senescent phenotype, and activate TGF-β1 and NF-κB signaling that could trigger inflammatory reaction in accelerated aging process. Hence, RAS antagonism through administration of ACEI/ARB improves mitochondrial function and exerts antioxidative effects and displays age-retarding benefits.

26Recently, Luo et al. reported that Wnt9a has a decisive role in driving tubular senescence and renal fibrosis, as well as evoking cell communication between senescent tubular cells and interstitial fibroblasts. Although not studied in their studies, RAS activation is supposed to play a role in Wnt9a-induced cellular senescence. Supporting the presumption, several studies point out the benefits of inhibiting the RAS system in organ aging process. The related mechanisms involve the upregulation of prosurvival nicotinamide phosphoribosyltransferase gene (Nampt) and downregulation of p16INK4A expression, as well as the improvement of mitochondrial function.

3.7. Inflammation and Cellular Senescence

27Chronic inflammation is a pathological feature of various CKD. Notably, inflammation serves as an important factor for accelerated aging. Unregulated inflammation has a key role in the pathogenesis and progression of autoimmune diseases such as presenile dementia, osteoporosis, and atherosclerosis. Inflammation is also involved in the pathogenesis of obesity and diabetes and serves as an important mediator of aging. In addition, the senescence-associated decline of the adaptive immune system (immunosenescence) may further aggravate aging phenotypes at the systemic level because of the impaired immune surveillance. Moreover, senescent cells can secrete many proinflammatory factors, such as TNF-α, IL-6, PAI-1, and MCP-1, which may further aggravate inflammation. Recent studies show that AUF1, the mRNA decay factor, links inflammation and aging. Deficiency of AUF1 induces marked cellular senescence and premature aging phenotype.

28In diabetic nephropathy, the prominent inflammation is observed even in the beginning and ongoing stage of kidney injury. The upregulation of systemic and local renal inflammation occurs in the early stage of DN. In diabetic status, high glucose, AGEs, and oxidative stress could simultaneously induce the activation of NF-κB, a known transcriptional signature of inflammation. Through recruiting p300, NF-κB triggers the activation of downstream effector iNOS, a promoter of oxidative stress and inflammation that causes extensive nitrotyrosine (NT) in proteins. Genetic and pharmacological inhibition of NF-κB signaling prevent age-associated diseases including diabetic nephropathy and natural aging.

29Additionally, Nod-like receptor 3 (NLRP3) inflammasome also plays a role in the development of inflammation under diabetic setting. In response to diverse damage-associated molecular patterns (DAMPs) in aging, such as excess glucose, ceramides, amyloids, urate, and cholesterol crystals, NLRP3 inflammasome is intimately correlated with age-related diseases. The NLRP3 inflammasome could activate caspase-1, which stimulates the maturation and secretion of IL-1β and IL-18 through cleaving their precursors. Consequently, these proinflammatory cytokines accelerate the aging process through inhibiting autophagy. Conversely, the impaired autophagy could trigger the accumulation of inflammasome to create a reciprocal activation loop. Interestingly, inflammation could also interplay with many other mechanisms of cellular senescence such as telomere shortening, progressive DNA damage, oxidative stress, and altered epigenetics. These create an intricate network to induce cellular senescence in diabetic nephropathy.

3.8. Uremic Toxins and Cellular Senescence

30Uremic toxins are endogenous waste products of metabolism. They are cleared predominantly by the kidneys. Three subgroups of uremic wastes are classified: (i) small water-soluble molecules (MW < 500 Da) such as urea, creatinine, and phosphate; (ii) middle (MW500~5000 Da) and large molecules (MW > 5000 Da) such as parathyroid hormone (PTH), IL-6, fibroblast growth factor 23 (FGF23), AGEs, advanced oxidation protein products (AOPPs), and other peptides; and (iii) small molecules (MW < 500 Da) but with high protein-binding abilities such as indoles, phenols, polyamine, and cresols. Notably, the regular hemodialysis could only remove small molecules with the molecular weight lower than 500 Da. Furthermore, it is also difficult to remove protein-bound uremic toxins such as indoxyl sulfate (IS), p-cresyl sulfate (PCS), and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), due to their high protein-binding capability (90%) to plasma proteins. It is notable that the imbalance of gut microbiome in kidney diseases largely contributes to the formation and retention of uremic toxins, which would create a reciprocal activation loop that accelerates the progression of kidney diseases.

31Uremic toxins could trigger senescence in various types of renal cells such as the proximal tubular cells and endothelial cells through multiple mechanisms. The most commonly studied pathway is oxidative stress-induced NF-κB signaling. However, other mechanisms are also contributed. Some reports show that uremic wastes could induce mitochondrial dysfunction and hypermethylation in Klotho gene, the two main mechanisms of cellular senescence in DN. As the well-known uremic toxins in DN, AGEs account for various mechanisms of cellular senescence. Although their detrimental role is firstly found in the longevity of C. elegans, AGEs show the active role in promoting senescence phenotype in multiple organ systems including the kidneys in humans. Studies show that AGEs trigger cellular senescence via oxidative stress-dependent p21 activation and p16 expression, inhibition of autophagy through reducing PINK1/Parkin, and promotion of inflammation in renal cells and others.

32Taken together, the accumulation of uremic toxins would influence cellular senescence nearly in all aspects of mechanisms, which cooperatively and reciprocally promote and accelerate cellular senescence that contributes to the pathogenesis of DN.

4. Therapeutic Potentials

33The therapeutic methods for DN nowadays refer to anti-RAS therapy using ACE inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and glucose control. However, anti-RAS therapy only displays limited efficacy, partly because of the compensatory upregulation of renin expression. Due to the metabolic memory of prior exposure to hyperglycemia, a single control of glucose fails to prevent the progression of kidney disease. Notably, several theoretical approaches might be applicable to target the aging process in DN (Figure 2).

34It is well known that calorie restriction (CR) reduces oxidative stress and proinflammatory injury. In addition, CR modulates mitochondrial activity and increases the autophagy activity, thereby extending health and lifespan. It has been shown that CR protects against cellular senescence through decreasing the expression of p16INK4A. Consequently, renal fibrosis is alleviated. Actually, CR inhibits cell senescence through various mechanisms. The most studied is the mammalian target of rapamycin (mTOR) signaling. CR could deactivate mTOR through activating AMP-activated protein kinase (AMPK). Several kinds of drugs targeting this pathway are effective in the retardation of aging and age-related disease. Rapamycin, the mTOR inhibitor, could protect cellular senescence and phosphate-induced premature aging. While AMPK activator metformin reduces ROS production in podocytes and prevents DN. Interestingly, long-term treatment with rapamycin may improve the quality of mtDNA in aging mice. However, long-term CR has a long way to achieve for clinical practice, especially in DN patients because of the limited daily nutrition. Another promising drug is sirtuin1 (SIRT1) agonist. As a NAD+-dependent deacetylase, SIRT1 plays an important role in the aging process and age-related phenotypes such as DN. SIRT1 could be induced by CR. The agonists of SIRT1 such as BF175 and resveratrol could greatly ameliorate the pathogenesis of diabetic kidney disease. And BF175 also shows less renal toxicity, suggesting the good prospects.

35Theoretically, antioxidants can mitigate ROS-induced damage, such as DNA mutations and protein modifications, as well as delay telomere shortening. However, the advantages of antioxidants are needed to be further clarified in aging-associated diseases. Chlorogenic acid could attenuate oxidative stress and inflammation in diabetic nephropathy, possibly through modulating Nrf2/HO-1 and NF-κB pathways. However, no direct evidences show its effects on aging retardation under the diabetic setting. Oppositely, the administration of mitochondria-targeted antioxidant MitoQ could dramatically ameliorate renal tubular injury in a diabetic mouse model. MitoQ reverses mitophagy through increasing the expression of PINK1 and Parkin. Another important study shows that Cu/Zn-superoxide dismutase 1 (SOD1), a strong endogenous antioxidant, has a new role in aging. Deficiency of SOD1 prolongs lifespan and retards the process of cellular senescence. Overexpression of SOD1 attenuates high glucose-induced endothelial cell senescence. These suggest that SOD1 may act as a promising therapeutic in DN through retarding aging. However, because of side-effects such as tumor genesis and difficulties to control the degree of antioxidation, the reasonable application should be closely noticed in therapy for patients.

36Another strategy to retard cellular senescence is the removal of these cells by senolytics, a new kind of drugs with the ability to slow the aging process. Many of these agents could induce the clearance of senescent cells through upregulation of antiapoptosis systems such as the BCL-2 family of proteins (BCL-2, BCL-XL, and BCL-W). The new senolytic molecules navitoclax and ABT-737 could occupy the inhibitory binding grooves of BCL-2, BCL-XL, and BCL-W, which counteract their antiapoptotic functions and initiate apoptosis in senescent cells. Furthermore, immune surveillance and genetic deletion of senescence-associated factor p16INK4a could also help to enhance the removal of senescent cells.

37SASP modulation has also been proposed as a way to slow the aging process. SASP blockade would be another attractive treatment option. However, the interventions of proinflammatory pathways such as NF-κB, p38-MAPK, or MAPK-activated protein kinase 2 could also influence the communications among healthy cells. Notably, a recent finding shows that bromodomain-containing protein 4 (BRD4) inhibitors could modulate SASP with high specificity in senescent cells without influencing healthy subjects. In histones, BRD4 binds to acetylated lysines, which results in the opening of chromatin and the activation of SASP process. BRD4 inhibitors JQ1 and iBET are recently studied and found to be prospective in therapeutic of aging.

38Restoration of endogenous Klotho or supplementation with exogenous Klotho could be a substitute therapeutic strategy for antiaging. Klotho could block Wnt/β-catenin signaling and its targets such as the renin-angiotensin system (RAS) and modulate the homeostasis of blood phosphate and vitamin D. In the aging process, Klotho gene displays hypermethylation. Notably, Ang II type 1 receptor antagonist (AT1R) losartan could alter the posttranslational modifications on histones, suggesting a protective role in Klotho gene stability. In addition, some drugs such as sulodexide and osthole may enhance the expression of Klotho to prevent the progression of DN. Considering the side-effects and toxicity of these molecular compounds, the direct supplement of Klotho may be the best way to provide renoprotecion. However, the clinical application of direct Klotho supplement is very limited because Klotho protein is with large molecular weight and complex structure. It is still promising that scientists are developing the small molecular peptides from the binding sites of Klotho with Wnt3a and other Wnts, suggesting the prospects for future clinical application.

39The latest topics of therapeutics in aging are stem cell therapy. A study shows that the injection of plasma from young mice into the circulation of aged mice induces a more youthful state. Furthermore, early-in-life genetic manipulations could preserve the proliferative ability of the gut stem cells, which leads to lifespan extension. In kidney disease, the supplement of mesenchymal stem cells (MSC) could prompt functional recovery. Even in aged stem cells, incubation of young blood could still ameliorate the functional deficits, suggesting the important role of microenvironment in stem cell renewal. Other studies also show that human umbilical cord-derived mesenchymal stromal cells could ameliorate renal fibrosis and cellular senescence and interestingly increase the expression of Klotho. Regenerative therapies by exogenous stem cell transplantation into damaged tissues could improve natural aging and stress-induced premature senescence (SIPS). However, the stem cell transplantation in humans is more challenging because of the unpredicted disadvantages such as tumor genesis and needs to be demonstrated repeatedly.

40Removal of uremic toxins may be a fundamental resolution strategy for retarding cellular senescence in DN. Some researchers are focusing on the improvement of protein-bound uremic waste clearance through intravenous lipid emulsion or infusion of a binding competitor ibuprofen in conventional dialysis therapies. Although these strategies present benefits, they are still in the primary stage of research. Compared with the controlling in the clearance, to decrease the generation of uremic wastes through the modulation of beneficial gut microbiota members may be more important. It is proved in long-term safety and presents improved removal of BUN when probiotics is supplemented to the therapies for CKD patients. Furthermore, synbiotics, resistant starch, and other dietary fiber could also help to decrease the production of uremic toxins through modifying gut microbial dysbiosis in CKD patients, thereby ameliorating oxidative stress and inflammation. However, the formulation of a probiotic bacteria and the detailed therapies in clinic need to be further studied, and the safety is also an important question to be resolved.

5. Conclusion

41In summary, we show the multiple mechanisms underscoring cell senescence network in diabetic nephropathy, which involve telomere shortening, DNA damage, epigenetic alterations, mitophagy deficiency, loss of Klotho, Wnt/β-catenin signaling activation, inflammation, and the accumulation of uremic toxins. These factors mutually affect and cooperatively promote cellular senescence in DN. Although some therapeutic methods are promising, the practical application in DN patients needs to be testified by large amounts of animal experiments and preclinical investigations. Notably, the long-term observation of antiaging therapy such as senolytics and stem cell transplantation could not be neglected. Recently, genome editing is attracting the notice of scientists. However, although with the prospective aspects, genome editing would bring out the problems of ethics in humanity. This should be particularly focused. Last, precision medicine therapy for individual DN patient should be considered in the therapeutic strategies of nephrologists. Nevertheless, targeted inhibition of cellular senescence provides important clues for clinical strategies for diabetic nephropathy.

References 240

1.
Bell S., Fletcher E. H., Brady I., et al. End-stage renal disease and survival in people with diabetes: a national database linkage study. QJM. 2015;108(2):127-134.
Not in our library10.1093/qjmed/hcu170
2.
Kato M., Natarajan R. Diabetic nephropathy—emerging epigenetic mechanisms. Nature Reviews Nephrology. 2014;10(9):517-530.
Not in our library10.1038/nrneph.2014.116
3.
Diabetes—Fact Sheet No. 312. 2015.
Not in our library
4.
Heerspink H. J. L., Parving H. H., Andress D. L., et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet. 2019;393(10184):1937-1947.
Not in our library10.1016/s0140-6736(19)30772-x
5.
Rao Kondapally Seshasai S., Kaptoge S., Thompson A., et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. New England Journal of Medicine. 2011;364(9):829-841.
Not in our library10.1056/nejmoa1008862
6.
Cao Z., Cooper M. E. Pathogenesis of diabetic nephropathy. Journal of Diabetes Investigation. 2011;2(4):243-247.
Not in our library10.1111/j.2040-1124.2011.00131.x
7.
Kumar Pasupulati A., Chitra P. S., Reddy G. B. Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy. Biomolecular Concepts. 2016;7(5-6):293-309.
Not in our library10.1515/bmc-2016-0021
8.
Cooper M. E. Diabetes: treating diabetic nephropathy-still an unresolved issue. Nature Reviews. Endocrinology. 2012;8(9):515-516.
Not in our library10.1038/nrendo.2012.125
9.
Chan G. C. W., Tang S. C. W. Diabetic nephropathy: landmark clinical trials and tribulations. Nephrology, Dialysis, Transplantation. 2016;31(3):359-368.
Not in our library10.1093/ndt/gfu411
10.
Mora-Fernández C., Domínguez-Pimentel V., de Fuentes M. M., Górriz J. L., Martínez-Castelao A., Navarro-González J. F. Diabetic kidney disease: from physiology to therapeutics. The Journal of Physiology. 2014;592(18):3997-4012.
Not in our library10.1113/jphysiol.2014.272328
11.
Hommos M. S., Glassock R. J., Rule A. D. Structural and functional changes in human kidneys with healthy aging. Journal of the American Society of Nephrology. 2017;28(10):2838-2844.
Not in our library10.1681/asn.2017040421
12.
Rule A. D., Amer H., Cornell L. D., et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Annals of Internal Medicine. 2010;152(9):561-567.
Not in our library10.7326/0003-4819-152-9-201005040-00006
13.
Liu J., Yang J. R., Chen X. M., Cai G. Y., Lin L. R., He Y. N. Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy. American Journal of Physiology. Cell Physiology. 2015;308(8):C621-C630.
Not in our library10.1152/ajpcell.00096.2014
14.
Marmary Y., Adar R., Gaska S., et al. Radiation-induced loss of salivary gland function is driven by cellular senescence and prevented by IL6 modulation. Cancer Research. 2016;76(5):1170-1180.
Not in our library10.1158/0008-5472.can-15-1671
15.
Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues · 2012
No notice
16.
Dimri G. P., Lee X., Basile G., et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(20):9363-9367.
Not in our library10.1073/pnas.92.20.9363
17.
Tchkonia T., Zhu Y., van Deursen J., Campisi J., Kirkland J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. The Journal of Clinical Investigation. 2013;123(3):966-972.
Not in our library10.1172/jci64098
18.
López-Otín C., Blasco M. A., Partridge L., Serrano M., Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194-1217.
Not in our library10.1016/j.cell.2013.05.039
19.
Wang W. J., Cai G. Y., Chen X. M. Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget. 2017;8(38):64520-64533.
Not in our library10.18632/oncotarget.17327
20.
Prattichizzo F., de Nigris V., Mancuso E., et al. Short-term sustained hyperglycaemia fosters an archetypal senescence-associated secretory phenotype in endothelial cells and macrophages. Redox Biology. 2018;15:170-181.
Not in our library10.1016/j.redox.2017.12.001
21.
D’Onofrio N., Servillo L., Giovane A., et al. Ergothioneine oxidation in the protection against high-glucose induced endothelial senescence: involvement of SIRT1 and SIRT6. Free Radical Biology & Medicine. 2016;96:211-222.
Not in our library10.1016/j.freeradbiomed.2016.04.013
22.
Kitada K., Nakano D., Ohsaki H., et al. Hyperglycemia causes cellular senescence via a SGLT2- and p21-dependent pathway in proximal tubules in the early stage of diabetic nephropathy. Journal of Diabetes and its Complications. 2014;28(5):604-611.
Not in our library10.1016/j.jdiacomp.2014.05.010
23.
van Deursen J. M. The role of senescent cells in ageing. Nature. 2014;509(7501):439-446.
Not in our library10.1038/nature13193
24.
Zhang X., Chen X., Wu D., et al. Downregulation of connexin 43 expression by high glucose induces senescence in glomerular mesangial cells. Journal of the American Society of Nephrology. 2006;17(6):1532-1542.
Not in our library10.1681/asn.2005070776
25.
Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy · 2018
No notice
26.
Fu B., Yang J., Chen J., et al. Preventive effect of Shenkang injection against high glucose-induced senescence of renal tubular cells. Frontiers in Medicine. 2019;13(2):267-276.
Not in our library10.1007/s11684-017-0586-8
27.
Tamura Y., Takubo K., Aida J., Araki A., Ito H. Telomere attrition and diabetes mellitus. Geriatrics & Gerontology International. 2016;16(Supplement 1):66-74.
Not in our library10.1111/ggi.12738
28.
Verzola D., Gandolfo M. T., Gaetani G., et al. Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy. American Journal of Physiology. Renal Physiology. 2008;295(5):F1563-F1573.
Not in our library10.1152/ajprenal.90302.2008
29.
Bernet J. D., Doles J. D., Hall J. K., Kelly Tanaka K., Carter T. A., Olwin B. B. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nature Medicine. 2014;20(3):265-271.
Not in our library10.1038/nm.3465
30.
Cosgrove B. D., Gilbert P. M., Porpiglia E., et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nature Medicine. 2014;20(3):255-264.
Not in our library10.1038/nm.3464
31.
García-Prat L., Martínez-Vicente M., Perdiguero E., et al. Autophagy maintains stemness by preventing senescence. Nature. 2016;529(7584):37-42.
Not in our library10.1038/nature16187
32.
Choudhury A. R., Ju Z., Djojosubroto M. W., et al. Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nature Genetics. 2007;39(1):99-105.
Not in our library10.1038/ng1937
33.
Chade A. R., Zhu X. Y., Krier J. D., et al. Endothelial progenitor cells homing and renal repair in experimental renovascular disease. Stem Cells. 2010;28(6):1039-1047.
Not in our library10.1002/stem.426
34.
Bartek J., Hodny Z. Old blood stem cells feel the stress. Nature. 2014;512(7513):140-141.
Not in our library10.1038/nature13652
35.
Niccoli T., Partridge L. Ageing as a risk factor for disease. Current Biology. 2012;22(17):R741-R752.
Not in our library10.1016/j.cub.2012.07.024
36.
Ovadya Y., Krizhanovsky V. Senescent cells: SASPected drivers of age-related pathologies. Biogerontology. 2014;15(6):627-642.
Not in our library10.1007/s10522-014-9529-9
37.
Colgin L. M., Baran K., Baumann P., Cech T. R., Reddel R. R. Human POT1 facilitates telomere elongation by telomerase. Current Biology. 2003;13(11):942-946.
Not in our library10.1016/s0960-9822(03)00339-7
38.
Blackburn E. H. Switching and signaling at the telomere. Cell. 2001;106(6):661-673.
Not in our library10.1016/s0092-8674(01)00492-5
39.
Sutanto S. S. I., McLennan S. V., Keech A. C., Twigg S. M. Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate. Journal of Cell Communication and Signaling. 2019.
Not in our library10.1007/s12079-019-00521-x
40.
Cumulative Inflammatory Load Is Associated with Short Leukocyte Telomere Length in the Health, Aging and Body Composition Study · 2011
No notice
41.
Carrero J. J., Stenvinkel P., Fellström B., et al. Telomere attrition is associated with inflammation, low fetuin-A levels and high mortality in prevalent haemodialysis patients. Journal of Internal Medicine. 2008;263(3):302-312.
Not in our library10.1111/j.1365-2796.2007.01890.x
42.
Houben J. M. J., Moonen H. J. J., van Schooten F. J., Hageman G. J. Telomere length assessment: biomarker of chronic oxidative stress? Free Radical Biology & Medicine. 2008;44(3):235-246.
Not in our library10.1016/j.freeradbiomed.2007.10.001
43.
Kurz D. J., Decary S., Hong Y., Trivier E., Akhmedov A., Erusalimsky J. D. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. Journal of Cell Science. 2004;117(11):2417-2426.
Not in our library10.1242/jcs.01097
44.
Jennings B. J., Ozanne S. E., Dorling M. W., Hales C. N. Early growth determines longevity in male rats and may be related to telomere shortening in the kidney. FEBS Letters. 1999;448(1):4-8.
Not in our library10.1016/s0014-5793(99)00336-1
45.
Fyhrquist F., Tiitu A., Saijonmaa O., Forsblom C., Groop P. H., on behalf of the FinnDiane Study Group. Telomere length and progression of diabetic nephropathy in patients with type 1 diabetes. Journal of Internal Medicine. 2010;267(3):278-286.
Not in our library10.1111/j.1365-2796.2009.02139.x
46.
Sampson M. J., Hughes D. A. Chromosomal telomere attrition as a mechanism for the increased risk of epithelial cancers and senescent phenotypes in type 2 diabetes. Diabetologia. 2006;49(8):1726-1731.
Not in our library10.1007/s00125-006-0322-4
47.
Noonan J. E., Jenkins A. J., Ma J. X., Keech A. C., Wang J. J., Lamoureux E. L. An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes. Diabetes. 2013;62(12):3968-3975.
Not in our library10.2337/db13-0800
48.
Cao D. W., Jiang C. M., Wan C., et al. Upregulation of MiR-126 delays the senescence of human glomerular mesangial cells induced by high glucose via telomere-p53-p21-Rb signaling pathway. Current Medical Science. 2018;38(5):758-764.
Not in our library10.1007/s11596-018-1942-x
49.
Bhattacharyya J., Mihara K., Bhattacharjee D., Mukherjee M. Telomere length as a potential biomarker of coronary artery disease. The Indian Journal of Medical Research. 2017;145(6):730-737.
Not in our library10.4103/0971-5916.216974
50.
Mazidi M., Rezaie P., Covic A., et al. Telomere attrition, kidney function, and prevalent chronic kidney disease in the United States. Oncotarget. 2017;8(46):80175-80181.
Not in our library10.18632/oncotarget.20706
51.
Failla G. The aging process and cancerogenesis. Annals of the New York Academy of Sciences. 1958;71(6):1124-1140.
Not in our library10.1111/j.1749-6632.1958.tb46828.x
52.
Shaulian E., Schreiber M., Piu F., Beeche M., Wagner E. F., Karin M. The mammalian UV response: c-Jun induction is required for exit from p53-imposed growth arrest. Cell. 2000;103(6):897-908.
Not in our library10.1016/s0092-8674(00)00193-8
53.
Webley K., Bond J. A., Jones C. J., et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Molecular and Cellular Biology. 2000;20(8):2803-2808.
Not in our library10.1128/mcb.20.8.2803-2808.2000
54.
Ge H., Ni S., Wang X., et al. Dexamethasone reduces sensitivity to cisplatin by blunting p53-dependent cellular senescence in non-small cell lung cancer. PLoS One. 2012;7(12, article e51821).
Not in our library10.1371/journal.pone.0051821
55.
Di Micco R., Fumagalli M., Cicalese A., et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature. 2006;444(7119):638-642.
Not in our library10.1038/nature05327
56.
Lans H., Hoeijmakers J. H. Genome stability, progressive kidney failure and aging. Nature Genetics. 2012;44(8):836-838.
Not in our library10.1038/ng.2363
57.
Al-Hussaini H., Kilarkaje N. Trans-resveratrol mitigates type 1 diabetes-induced oxidative DNA damage and accumulation of advanced glycation end products in glomeruli and tubules of rat kidneys. Toxicology and Applied Pharmacology. 2018;339:97-109.
Not in our library10.1016/j.taap.2017.11.025
58.
Campisi J. Aging, cellular senescence, and cancer. Annual Review of Physiology. 2013;75(1):685-705.
Not in our library10.1146/annurev-physiol-030212-183653
59.
DNA methylation age of human tissues and cell types · 2013
Corrected
60.
Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693-705.
Not in our library10.1016/j.cell.2007.02.005
61.
Portela A., Esteller M. Epigenetic modifications and human disease. Nature Biotechnology. 2010;28(10):1057-1068.
Not in our library10.1038/nbt.1685
62.
Jones P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews. Genetics. 2012;13(7):484-492.
Not in our library10.1038/nrg3230
63.
Peschansky V. J., Wahlestedt C. Non-coding RNAs as direct and indirect modulators of epigenetic regulation. Epigenetics. 2014;9(1):3-12.
Not in our library10.4161/epi.27473
64.
Strahl B. D., Allis C. D. The language of covalent histone modifications. Nature. 2000;403(6765):41-45.
Not in our library10.1038/47412
65.
Bird A. P., Wolffe A. P. Methylation-induced repression--belts, braces, and chromatin. Cell. 1999;99(5):451-454.
Not in our library10.1016/s0092-8674(00)81532-9
66.
Zhou V. W., Goren A., Bernstein B. E. Charting histone modifications and the functional organization of mammalian genomes. Nature Reviews. Genetics. 2011;12(1):7-18.
Not in our library10.1038/nrg2905
67.
Marumo T., Yagi S., Kawarazaki W., et al. Diabetes induces aberrant DNA methylation in the proximal tubules of the kidney. Journal of the American Society of Nephrology. 2015;26(10):2388-2397.
Not in our library10.1681/asn.2014070665
68.
Hasegawa K., Wakino S., Simic P., et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nature Medicine. 2013;19(11):1496-1504.
Not in our library10.1038/nm.3363
69.
Siddiqi F. S., Majumder S., Thai K., et al. The histone methyltransferase enzyme enhancer of zeste homolog 2 protects against podocyte oxidative stress and renal injury in diabetes. Journal of the American Society of Nephrology. 2016;27(7):2021-2034.
Not in our library10.1681/asn.2014090898
70.
de Marinis Y., Cai M., Bompada P., et al. Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney. Kidney International. 2016;89(2):342-353.
Not in our library10.1016/j.kint.2015.12.018
71.
Paneni F., Mocharla P., Akhmedov A., et al. Gene silencing of the mitochondrial adaptor p66Shc suppresses vascular hyperglycemic memory in diabetes. Circulation Research. 2012;111(3):278-289.
Not in our library10.1161/circresaha.112.266593
72.
Bock F., Shahzad K., Wang H., et al. Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(2):648-653.
Not in our library10.1073/pnas.1218667110
73.
Giorgio M., Migliaccio E., Orsini F., et al. Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell. 2005;122(2):221-233.
Not in our library10.1016/j.cell.2005.05.011
74.
Zhong Q., Kowluru R. A. Epigenetic modification of Sod2 in the development of diabetic retinopathy and in the metabolic memory: role of histone methylation. Investigative Ophthalmology & Visual Science. 2013;54(1):244-250.
Not in our library10.1167/iovs.12-10854
75.
el-Osta A., Brasacchio D., Yao D., et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. The Journal of Experimental Medicine. 2008;205(10):2409-2417.
Not in our library10.1084/jem.20081188
76.
Brasacchio D., Okabe J., Tikellis C., et al. Hyperglycemia induces a dynamic cooperativity of histone methylase and demethylase enzymes associated with gene-activating epigenetic marks that coexist on the lysine tail. Diabetes. 2009;58(5):1229-1236.
Not in our library10.2337/db08-1666
77.
Okabe J., Orlowski C., Balcerczyk A., et al. Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells. Circulation Research. 2012;110(8):1067-1076.
Not in our library10.1161/circresaha.112.266171
78.
Paneni F., Costantino S., Battista R., et al. Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus. Circulation. Cardiovascular Genetics. 2015;8(1):150-158.
Not in our library10.1161/circgenetics.114.000671
79.
Villeneuve L. M., Kato M., Reddy M. A., Wang M., Lanting L., Natarajan R. Enhanced levels of microRNA-125b in vascular smooth muscle cells of diabetic db/db mice lead to increased inflammatory gene expression by targeting the histone methyltransferase Suv39h1. Diabetes. 2010;59(11):2904-2915.
Not in our library10.2337/db10-0208
80.
Bhatt K., Lanting L. L., Jia Y., et al. Anti-inflammatory role of microRNA-146a in the pathogenesis of diabetic nephropathy. Journal of the American Society of Nephrology. 2016;27(8):2277-2288.
Not in our library10.1681/asn.2015010111
81.
Wang X., Liu J., Zhen J., et al. Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney International. 2014;86(4):712-725.
Not in our library10.1038/ki.2014.111
82.
Lin W., Zhang Q., Liu L., Yin S., Liu Z., Cao W. Klotho restoration via acetylation of peroxisome proliferation–activated receptor γ reduces the progression of chronic kidney disease. Kidney International. 2017;92(3):669-679.
Not in our library10.1016/j.kint.2017.02.023
83.
Forster M. J., Dubey A., Dawson K. M., Stutts W. A., Lal H., Sohal R. S. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Proceedings of the National Academy of Sciences of the United States of America. 1996;93(10):4765-4769.
Not in our library10.1073/pnas.93.10.4765
84.
Morais V. A., Haddad D., Craessaerts K., et al. PINK1 loss-of-function mutations affect mitochondrial complex I activity via NdufA10 ubiquinone uncoupling. Science. 2014;344(6180):203-207.
Not in our library10.1126/science.1249161
85.
Barja G. Updating the mitochondrial free radical theory of aging: an integrated view, key aspects, and confounding concepts. Antioxidants & Redox Signaling. 2013;19(12):1420-1445.
Not in our library10.1089/ars.2012.5148
86.
Conley K. E., Marcinek D. J., Villarin J. Mitochondrial dysfunction and age. Current Opinion in Clinical Nutrition and Metabolic Care. 2007;10(6):688-692.
Not in our library10.1097/mco.0b013e3282f0dbfb
87.
Edgar D., Shabalina I., Camara Y., et al. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metabolism. 2009;10(2):131-138.
Not in our library10.1016/j.cmet.2009.06.010
88.
Sharma K., Karl B., Mathew A. V., et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. Journal of the American Society of Nephrology. 2013;24(11):1901-1912.
Not in our library10.1681/asn.2013020126
89.
Scialò F., Sriram A., Fernández-Ayala D., et al. Mitochondrial ROS produced via reverse electron transport extend animal lifespan. Cell Metabolism. 2016;23(4):725-734.
Not in our library10.1016/j.cmet.2016.03.009
90.
Lee S. J., Hwang A. B., Kenyon C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Current Biology. 2010;20(23):2131-2136.
Not in our library10.1016/j.cub.2010.10.057
91.
A Mitochondrial Superoxide Signal Triggers Increased Longevity in Caenorhabditis elegans · 2010
No notice
92.
Yang W., Hekimi S. Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell. 2010;9(3):433-447.
Not in our library10.1111/j.1474-9726.2010.00571.x
93.
Schmeisser S., Priebe S., Groth M., et al. Neuronal ROS signaling rather than AMPK/sirtuin-mediated energy sensing links dietary restriction to lifespan extension. Molecular Metabolism. 2013;2(2):92-102.
Not in our library10.1016/j.molmet.2013.02.002
94.
DeBalsi K. L., Hoff K. E., Copeland W. C. Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Research Reviews. 2017;33:89-104.
Not in our library10.1016/j.arr.2016.04.006
95.
Hashizume O., Shimizu A., Yokota M., et al. Specific mitochondrial DNA mutation in mice regulates diabetes and lymphoma development. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(26):10528-10533.
Not in our library10.1073/pnas.1202367109
96.
Kauppila T. E. S., Bratic A., Jensen M. B., et al. Mutations of mitochondrial DNA are not major contributors to aging of fruit flies. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(41):E9620-e9629.
Not in our library10.1073/pnas.1721683115
97.
Diot A., Morten K., Poulton J. Mitophagy plays a central role in mitochondrial ageing. Mammalian Genome. 2016;27(7-8):381-395.
Not in our library10.1007/s00335-016-9651-x
98.
Aggarwal S., Mannam P., Zhang J. Differential regulation of autophagy and mitophagy in pulmonary diseases. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2016;311(2):L433-L452.
Not in our library10.1152/ajplung.00128.2016
99.
Liang Q., Kobayashi S. Mitochondrial quality control in the diabetic heart. Journal of Molecular and Cellular Cardiology. 2016;95:57-69.
Not in our library10.1016/j.yjmcc.2015.12.025
100.
Zhan M., Usman I. M., Sun L., Kanwar Y. S. Disruption of renal tubular mitochondrial quality control by Myo-inositol oxygenase in diabetic kidney disease. Journal of the American Society of Nephrology. 2015;26(6):1304-1321.
Not in our library10.1681/asn.2014050457
101.
Guo K., Lu J., Huang Y., et al. Protective role of PGC-1α in diabetic nephropathy is associated with the inhibition of ROS through mitochondrial dynamic remodeling. PLoS One. 2015;10(4, article e0125176).
Not in our library10.1371/journal.pone.0125176
102.
Wauer T., Simicek M., Schubert A., Komander D. Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature. 2015;524(7565):370-374.
Not in our library10.1038/nature14879
103.
Lazarou M., Sliter D. A., Kane L. A., et al. The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature. 2015;524(7565):309-314.
Not in our library10.1038/nature14893
104.
Wong Y. C., Holzbaur E. L. F. Temporal dynamics of PARK2/parkin and OPTN/optineurin recruitment during the mitophagy of damaged mitochondria. Autophagy. 2015;11(2):422-424.
Not in our library10.1080/15548627.2015.1009792
105.
Greene J. C., Whitworth A. J., Kuo I., Andrews L. A., Feany M. B., Pallanck L. J. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences of the United States of America. 2003;100(7):4078-4083.
Not in our library10.1073/pnas.0737556100
106.
Rana A., Rera M., Walker D. W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(21):8638-8643.
Not in our library10.1073/pnas.1216197110
107.
Xiao L., Xu X., Zhang F., et al. The mitochondria-targeted antioxidant MitoQ ameliorated tubular injury mediated by mitophagy in diabetic kidney disease via Nrf2/PINK1. Redox Biology. 2017;11:297-311.
Not in our library10.1016/j.redox.2016.12.022
108.
Autophagy Attenuates Diabetic Glomerular Damage through Protection of Hyperglycemia-Induced Podocyte Injury · 2013
No notice
109.
Xu Y., Sun Z. Molecular basis of klotho: from gene to function in aging. Endocrine Reviews. 2015;36(2):174-193.
Not in our library10.1210/er.2013-1079
110.
Olauson H., Vervloet M. G., Cozzolino M., Massy Z. A., Ureña Torres P., Larsson T. E. New insights into the FGF23-klotho axis. Seminars in Nephrology. 2014;34(6):586-597.
Not in our library10.1016/j.semnephrol.2014.09.005
111.
New Insights into the Mechanism of Action of Soluble Klotho · 2017
No notice
112.
Drew D. A., Katz R., Kritchevsky S., et al. Association between soluble klotho and change in kidney function: the health aging and body composition study. Journal of the American Society of Nephrology. 2017;28(6):1859-1866.
Not in our library10.1681/asn.2016080828
113.
Olauson H., Larsson T. E. FGF23 and klotho in chronic kidney disease. Current Opinion in Nephrology and Hypertension. 2013;22(4):397-404.
Not in our library10.1097/mnh.0b013e32836213ee
114.
Kops G. J. P. L., Dansen T. B., Polderman P. E., et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature. 2002;419(6904):316-321.
Not in our library10.1038/nature01036
115.
Zhao Y., Banerjee S., Dey N., et al. Klotho depletion contributes to increased inflammation in kidney of the db/db mouse model of diabetes via RelA (serine)536 phosphorylation. Diabetes. 2011;60(7):1907-1916.
Not in our library10.2337/db10-1262
116.
Buendía P., Carracedo J., Soriano S., et al. Klotho prevents NFκB translocation and protects endothelial cell from senescence induced by uremia. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2015;70(10):1198-1209.
Not in our library10.1093/gerona/glu170
117.
Sugiura H., Yoshida T., Shiohira S., et al. Reduced klotho expression level in kidney aggravates renal interstitial fibrosis. American Journal of Physiology. Renal Physiology. 2012;302(10):F1252-F1264.
Not in our library10.1152/ajprenal.00294.2011
118.
Sopjani M., Rinnerthaler M., Kruja J., Dermaku-Sopjani M. Intracellular signaling of the aging suppressor protein klotho. Current Molecular Medicine. 2015;15(1):27-37.
Not in our library10.2174/1566524015666150114111258
119.
Hu M. C., Shi M., Zhang J., et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. The FASEB Journal. 2010;24(9):3438-3450.
Not in our library10.1096/fj.10-154765
120.
Urakawa I., Yamazaki Y., Shimada T., et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006;444(7120):770-774.
Not in our library10.1038/nature05315
121.
Ohnishi M., Razzaque M. S. Dietary and genetic evidence for phosphate toxicity accelerating mammalian aging. The FASEB Journal. 2010;24(9):3562-3571.
Not in our library10.1096/fj.09-152488
122.
Kuro-o M. A potential link between phosphate and aging--lessons from klotho-deficient mice. Mechanisms of Ageing and Development. 2010;131(4):270-275.
Not in our library10.1016/j.mad.2010.02.008
123.
Asai O., Nakatani K., Tanaka T., et al. Decreased renal α-klotho expression in early diabetic nephropathy in humans and mice and its possible role in urinary calcium excretion. Kidney International. 2012;81(6):539-547.
Not in our library10.1038/ki.2011.423
124.
Cheng M. F., Chen L. J., Cheng J. T. Decrease of klotho in the kidney of streptozotocin-induced diabetic rats. Journal of Biomedicine & Biotechnology. 2010;2010:7.
Not in our library10.1155/2010/513853
125.
Young G. H., Wu V. C. KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney International. 2012;81(7):611-612.
Not in our library10.1038/ki.2011.461
126.
Sun C. Y., Chang S. C., Wu M. S. Suppression of klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney International. 2012;81(7):640-650.
Not in our library10.1038/ki.2011.445
127.
Moreno J. A., Izquierdo M. C., Sanchez-Niño M. D., et al. The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. Journal of the American Society of Nephrology. 2011;22(7):1315-1325.
Not in our library10.1681/asn.2010101073
128.
Troyano-Suárez N., del Nogal-Avila M., Mora I., et al. Glucose oxidase induces cellular senescence in immortal renal cells through ILK by downregulating klotho gene expression. Oxidative Medicine and Cellular Longevity. 2015;2015:13.
Not in our library10.1155/2015/416738
129.
Kuro-o M. Klotho as a regulator of oxidative stress and senescence. Biological Chemistry. 2008;389(3):233-241.
Not in our library10.1515/bc.2008.028
130.
He W., Kang Y. S., Dai C., Liu Y. Blockade of Wnt/β-catenin signaling by paricalcitol ameliorates proteinuria and kidney injury. Journal of the American Society of Nephrology. 2011;22(1):90-103.
Not in our library10.1681/asn.2009121236
131.
Zhou T., He X., Cheng R., et al. Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy. Diabetologia. 2012;55(1):255-266.
Not in our library10.1007/s00125-011-2314-2
132.
Heikkila E., Juhila J., Lassila M., et al. β-catenin mediates adriamycin-induced albuminuria and podocyte injury in adult mouse kidneys. Nephrology, Dialysis, Transplantation. 2010;25(8):2437-2446.
Not in our library10.1093/ndt/gfq076
133.
Xiao L., Zhou D., Tan R. J., et al. Sustained activation of Wnt/β-catenin signaling drives AKI to CKD progression. Journal of the American Society of Nephrology. 2016;27(6):1727-1740.
Not in our library10.1681/asn.2015040449
134.
Moon R. T., Bowerman B., Boutros M., Perrimon N. The promise and perils of Wnt signaling through β-catenin. Science. 2002;296(5573):1644-1646.
Not in our library10.1126/science.1071549
135.
Bienz M., Clevers H. Armadillo/β-catenin signals in the nucleus--proof beyond a reasonable doubt? Nature Cell Biology. 2003;5(3):179-182.
Not in our library10.1038/ncb0303-179
136.
Staal F. J. T., Clevers H. Tcf/Lef transcription factors during T-cell development: unique and overlapping functions. The Hematology Journal. 2000;1(1):3-6.
Not in our library10.1038/sj.thj.6200001
137.
Manolagas S. C., Almeida M. Gone with the Wnts: β-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Molecular Endocrinology. 2007;21(11):2605-2614.
Not in our library10.1210/me.2007-0259
138.
Essers M. A., de Vries-Smits L. M., Barker N., Polderman P. E., Burgering B. M., Korswagen H. C. Functional interaction between β-catenin and FOXO in oxidative stress signaling. Science. 2005;308(5725):1181-1184.
Not in our library10.1126/science.1109083
139.
Zhou L., Li Y., Hao S., et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling. Journal of the American Society of Nephrology. 2015;26(1):107-120.
Not in our library10.1681/asn.2014010085
140.
Yang S., Sun D., Wang L., et al. The role of STAT3/mTOR-regulated autophagy in angiotensin II-induced senescence of human glomerular mesangial cells. Cellular Signalling. 2019;53:327-338.
Not in our library10.1016/j.cellsig.2018.10.021
141.
Jiao S., Meng F., Zhang J., Yang X., Zheng X., Wang L. STAT1 mediates cellular senescence induced by angiotensin II and H2O2 in human glomerular mesangial cells. Molecular and Cellular Biochemistry. 2012;365(1-2):9-17.
Not in our library10.1007/s11010-011-1197-3
142.
Jiao S., Zheng X., Yang X., Zhang J., Wang L. Losartan inhibits STAT1 activation and protects human glomerular mesangial cells from angiotensin II induced premature senescence. Canadian Journal of Physiology and Pharmacology. 2012;90(1):89-98.
Not in our library10.1139/y11-105
143.
Zhou H., Huang B., Du J., Wang L. Role of the JAK2/STAT pathway and losartan in human glomerular mesangial cell senescence. Molecular Medicine Reports. 2010;3(3):393-398.
Not in our library10.3892/mmr_00000270
144.
Sangaralingham S. J., Wang B. H., Huang L., et al. Cardiorenal fibrosis and dysfunction in aging: imbalance in mediators and regulators of collagen. Peptides. 2016;76:108-114.
Not in our library10.1016/j.peptides.2016.01.004
145.
Lee M. Y., Wang Y., Vanhoutte P. M. Senescence of cultured porcine coronary arterial endothelial cells is associated with accelerated oxidative stress and activation of NFκB. Journal of Vascular Research. 2010;47(4):287-298.
Not in our library10.1159/000265563
146.
de Cavanagh E. M. V., Inserra F., Ferder L. Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria? Cardiovascular Research. 2010;89(1):31-40.
Not in our library10.1093/cvr/cvq285
147.
Luo C., Zhou S., Zhou Z., et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. Journal of the American Society of Nephrology. 2018;29(4):1238-1256.
Not in our library10.1681/asn.2017050574
148.
Benigni A., Cassis P., Remuzzi G. Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Molecular Medicine. 2010;2(7):247-257.
Not in our library10.1002/emmm.201000080
149.
Benigni A., Corna D., Zoja C., et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. The Journal of Clinical Investigation. 2009;119(3):524-530.
Not in our library10.1172/jci36703
150.
de Cavanagh E. M., Piotrkowski B., Basso N., et al. Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. The FASEB Journal. 2003;17(9):1096-1098.
Not in our library10.1096/fj.02-0063fje
151.
de Cavanagh E. M. V., Inserra F., Ferder M., Ferder L. From mitochondria to disease: role of the renin-angiotensin system. American Journal of Nephrology. 2007;27(6):545-553.
Not in our library10.1159/000107757
152.
Vajapey R., Rini D., Walston J., Abadir P. The impact of age-related dysregulation of the angiotensin system on mitochondrial redox balance. Frontiers in Physiology. 2014;5:p. 439.
Not in our library10.3389/fphys.2014.00439
153.
Brod S. A. Unregulated inflammation shortens human functional longevity. Inflammation Research. 2000;49(11):561-570.
Not in our library10.1007/s000110050632
154.
Nitta T., Kanoh H., Inamori K. I., Suzuki A., Takahashi T., Inokuchi J. I. Globo-series glycosphingolipids enhance Toll-like receptor 4-mediated inflammation and play a pathophysiological role in diabetic nephropathy. Glycobiology. 2019;29(3):260-268.
Not in our library10.1093/glycob/cwy105
155.
Barzilai N., Huffman D. M., Muzumdar R. H., Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61(6):1315-1322.
Not in our library10.2337/db11-1300
156.
Deeks S. G. HIV infection, inflammation, immunosenescence, and aging. Annual Review of Medicine. 2011;62(1):141-155.
Not in our library10.1146/annurev-med-042909-093756
157.
Pantsulaia I., Ciszewski W. M., Niewiarowska J. Senescent endothelial cells: potential modulators of immunosenescence and ageing. Ageing Research Reviews. 2016;29:13-25.
Not in our library10.1016/j.arr.2016.05.011
158.
Pont A. R., Sadri N., Hsiao S. J., Smith S., Schneider R. J. mRNA decay factor AUF1 maintains normal aging, telomere maintenance, and suppression of senescence by activation of telomerase transcription. Molecular Cell. 2012;47(1):5-15.
Not in our library10.1016/j.molcel.2012.04.019
159.
Li Y., Li X., He K., et al. C-peptide prevents NF-κB from recruiting p300 and binding to the inos promoter in diabetic nephropathy. The FASEB Journal. 2018;32(4):2269-2279.
Not in our library10.1096/fj.201700891r
160.
Tilstra J. S., Robinson A. R., Wang J., et al. NF-κB inhibition delays DNA damage-induced senescence and aging in mice. The Journal of Clinical Investigation. 2012;122(7):2601-2612.
Not in our library10.1172/jci45785
161.
Osorio F. G., Barcena C., Soria-Valles C., et al. Nuclear lamina defects cause ATM-dependent NF-κB activation and link accelerated aging to a systemic inflammatory response. Genes & Development. 2012;26(20):2311-2324.
Not in our library10.1101/gad.197954.112
162.
Adler A. S., Sinha S., Kawahara T. L. A., Zhang J. Y., Segal E., Chang H. Y. Motif module map reveals enforcement of aging by continual NF-κB activity. Genes & Development. 2007;21(24):3244-3257.
Not in our library10.1101/gad.1588507
163.
Lazaro I., Oguiza A., Recio C., et al. Targeting HSP90 ameliorates nephropathy and atherosclerosis through suppression of NF-κB and STAT signaling pathways in diabetic mice. Diabetes. 2015;64(10):3600-3613.
Not in our library10.2337/db14-1926
164.
Wu J., Guan T. J., Zheng S., et al. Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice. Laboratory Investigation. 2011;91(10):1459-1471.
Not in our library10.1038/labinvest.2011.93
165.
Zhou R., Yazdi A. S., Menu P., Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011;469(7329):221-225.
Not in our library10.1038/nature09663
166.
Goldberg E. L., Dixit V. D. Drivers of age-related inflammation and strategies for healthspan extension. Immunological Reviews. 2015;265(1):63-74.
Not in our library10.1111/imr.12295
167.
Schroder K., Tschopp J. The inflammasomes. Cell. 2010;140(6):821-832.
Not in our library10.1016/j.cell.2010.01.040
168.
Inflammaging: disturbed interplay between autophagy and inflammasomes · 2012
No notice
169.
Giacoppo S., Bramanti P., Mazzon E. Triggering of inflammasome by impaired autophagy in response to acute experimental Parkinson’s disease: involvement of the PI3K/Akt/mTOR pathway. NeuroReport. 2017;28(15):996-1007.
Not in our library10.1097/wnr.0000000000000871
170.
Duranton F., Cohen G., de Smet R., et al. Normal and pathologic concentrations of uremic toxins. Journal of the American Society of Nephrology. 2013;23(7):1258-1270.
Not in our library10.1681/asn.2011121175
171.
Pletinck A., Glorieux G., Schepers E., et al. Protein-bound uremic toxins stimulate crosstalk between leukocytes and vessel wall. Journal of the American Society of Nephrology. 2013;24(12):1981-1994.
Not in our library10.1681/asn.2012030281
172.
Jansen J., Jankowski J., Gajjala P. R., Wetzels J. F. M., Masereeuw R. Disposition and clinical implications of protein-bound uremic toxins. Clinical Science. 2017;131(14):1631-1647.
Not in our library10.1042/cs20160191
173.
Poesen R., Windey K., Neven E., et al. The influence of CKD on colonic microbial metabolism. Journal of the American Society of Nephrology. 2016;27(5):1389-1399.
Not in our library10.1681/asn.2015030279
174.
Shimizu H., Bolati D., Adijiang A., et al. Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. American Journal of Physiology. Cell Physiology. 2010;299(5):C1110-C1117.
Not in our library10.1152/ajpcell.00217.2010
175.
Shimizu H., Yisireyili M., Nishijima F., Niwa T. Stat3 contributes to indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence. American Journal of Nephrology. 2012;36(2):184-189.
Not in our library10.1159/000341515
176.
Yu M., Kim Y. J., Kang D. H. Indoxyl sulfate-induced endothelial dysfunction in patients with chronic kidney disease via an induction of oxidative stress. Clinical Journal of the American Society of Nephrology. 2011;6(1):30-39.
Not in our library10.2215/cjn.05340610
177.
Shen W. C., Liang C. J., Huang T. M., et al. Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway. Archives of Toxicology. 2016;90(11):2779-2792.
Not in our library10.1007/s00204-015-1652-0
178.
Sun C. Y., Cheng M. L., Pan H. C., Lee J. H., Lee C. C. Protein-bound uremic toxins impaired mitochondrial dynamics and functions. Oncotarget. 2017;8(44):77722-77733.
Not in our library10.18632/oncotarget.20773
179.
Morcos M., du X., Pfisterer F., et al. Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans. Aging Cell. 2008;7(2):260-269.
Not in our library10.1111/j.1474-9726.2008.00371.x
180.
Schlotterer A., Kukudov G., Bozorgmehr F., et al. C. elegans as model for the study of high glucose- mediated life span reduction. Diabetes. 2009;58(11):2450-2456.
Not in our library10.2337/db09-0567
181.
Semba R. D., Nicklett E. J., Ferrucci L. Does accumulation of advanced glycation end products contribute to the aging phenotype? The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2010;65A(9):963-975.
Not in our library10.1093/gerona/glq074
182.
Liu J., Huang K., Cai G. Y., et al. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cellular Signalling. 2014;26(1):110-121.
Not in our library10.1016/j.cellsig.2013.10.002
183.
Yamagishi S., Nakamura N., Suematsu M., Kaseda K., Matsui T. Advanced glycation end products: a molecular target for vascular complications in diabetes. Molecular Medicine. 2015;21(Supplement 1):S32-S40.
Not in our library10.2119/molmed.2015.00067
184.
Zha Z., Wang J., Wang X., Lu M., Guo Y. Involvement of PINK1/Parkin-mediated mitophagy in AGE-induced cardiomyocyte aging. International Journal of Cardiology. 2017;227:201-208.
Not in our library10.1016/j.ijcard.2016.11.161
185.
Shi M., Yang S., Zhu X., et al. The RAGE/STAT5/autophagy axis regulates senescence in mesangial cells. Cellular Signalling. 2019;62, article 109334.
Not in our library10.1016/j.cellsig.2019.05.019
186.
Chen Y. J., Chan D. C., Chiang C. K., et al. Advanced glycation end-products induced VEGF production and inflammatory responses in human synoviocytes via RAGE-NF-κB pathway activation. Journal of Orthopaedic Research. 2016;34(5):791-800.
Not in our library10.1002/jor.23083
187.
Nakamura T., Fujiwara N., Kawagoe Y., Sugaya T., Ueda Y., Koide H. Effects of telmisartan and enalapril on renoprotection in patients with mild to moderate chronic kidney disease. European Journal of Clinical Investigation. 2010;40(9):790-796.
Not in our library10.1111/j.1365-2362.2010.02319.x
188.
Tan X., He W., Liu Y. Combination therapy with paricalcitol and trandolapril reduces renal fibrosis in obstructive nephropathy. Kidney International. 2009;76(12):1248-1257.
Not in our library10.1038/ki.2009.346
189.
Zhang Z., Zhang Y., Ning G., Deb D. K., Kong J., Li Y. C. Combination therapy with AT1 blocker and vitamin D analog markedly ameliorates diabetic nephropathy: blockade of compensatory renin increase. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(41):15896-15901.
Not in our library10.1073/pnas.0803751105
190.
Chen Z., Miao F., Paterson A. D., et al. Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT/EDIC type 1 diabetes cohort. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(21):E3002-E3011.
Not in our library10.1073/pnas.1603712113
191.
Reddy M. A., Natarajan R. Epigenetics in diabetic kidney disease. Journal of the American Society of Nephrology. 2011;22(12):2182-2185.
Not in our library10.1681/asn.2011060629
192.
Ning Y. C., Cai G. Y., Zhuo L., et al. Short-term calorie restriction protects against renal senescence of aged rats by increasing autophagic activity and reducing oxidative damage. Mechanisms of Ageing and Development. 2013;134(11-12):570-579.
Not in our library10.1016/j.mad.2013.11.006
193.
Lopez-Lluch G., Navas P. Calorie restriction as an intervention in ageing. The Journal of Physiology. 2016;594(8):2043-2060.
Not in our library10.1113/jp270543
194.
Xu X. M., Ning Y. C., Wang W. J., et al. Anti-inflamm-aging effects of long-term caloric restriction via overexpression of SIGIRR to inhibit NF-κB signaling pathway. Cellular Physiology and Biochemistry. 2015;37(4):1257-1270.
Not in our library10.1159/000430248
195.
Inoki K., Kim J., Guan K. L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annual Review of Pharmacology and Toxicology. 2012;52(1):381-400.
Not in our library10.1146/annurev-pharmtox-010611-134537
196.
Iglesias-Bartolome R., Patel V., Cotrim A., et al. mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis. Cell Stem Cell. 2012;11(3):401-414.
Not in our library10.1016/j.stem.2012.06.007
197.
Kawai M., Kinoshita S., Ozono K., Michigami T. Inorganic phosphate activates the AKT/mTORC1 pathway and shortens the life span of an αKlotho-deficient model. Journal of the American Society of Nephrology. 2016;27(9):2810-2824.
Not in our library10.1681/asn.2015040446
198.
Bielas J., Herbst A., Widjaja K., et al. Long term rapamycin treatment improves mitochondrial DNA quality in aging mice. Experimental Gerontology. 2018;106:125-131.
Not in our library10.1016/j.exger.2018.02.021
199.
Guan Y., Wang S. R., Huang X. Z., et al. Nicotinamide mononucleotide, an NAD+ precursor, rescues age-associated susceptibility to AKI in a Sirtuin 1-dependent manner. Journal of the American Society of Nephrology. 2017;28(8):2337-2352.
Not in our library10.1681/asn.2016040385
200.
Kume S., Uzu T., Horiike K., et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. The Journal of Clinical Investigation. 2010;120(4):1043-1055.
Not in our library10.1172/jci41376
201.
Hong Q., Zhang L., Das B., et al. Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury. Kidney International. 2018;93(6):1330-1343.
Not in our library10.1016/j.kint.2017.12.008
202.
Antioxidant Supplementation in the Treatment of Aging-Associated Diseases · 2016
No notice
203.
Shevalye H., Lupachyk S., Watcho P., et al. Prediabetic nephropathy as an early consequence of the high-calorie/high-fat diet: relation to oxidative stress. Endocrinology. 2012;153(3):1152-1161.
Not in our library10.1210/en.2011-1997
204.
Al-Waili N., Al-Waili H., Al-Waili T., Salom K. Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials. Redox Report. 2017;22(3):99-118.
Not in our library10.1080/13510002.2017.1297885
205.
Tavafi M. Diabetic nephropathy and antioxidants. Journal of Nephropathology. 2013;2(1):20-27.
Not in our library10.5812/nephropathol.9093
206.
Bao L., Li J., Zha D., et al. Chlorogenic acid prevents diabetic nephropathy by inhibiting oxidative stress and inflammation through modulation of the Nrf2/HO-1 and NF-κB pathways. International Immunopharmacology. 2018;54:245-253.
Not in our library10.1016/j.intimp.2017.11.021
207.
Zhang Y., Unnikrishnan A., Deepa S. S., et al. A new role for oxidative stress in aging: the accelerated aging phenotype in Sod1−/− mice is correlated to increased cellular senescence. Redox Biology. 2017;11:30-37.
Not in our library10.1016/j.redox.2016.10.014
208.
Baker D. J., Wijshake T., Tchkonia T., et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-236.
Not in our library10.1038/nature10600
209.
Chang J., Wang Y., Shao L., et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine. 2016;22(1):78-83.
Not in our library10.1038/nm.4010
210.
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL · 2016
No notice
211.
Tse C., Shoemaker A. R., Adickes J., et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Research. 2008;68(9):3421-3428.
Not in our library10.1158/0008-5472.can-07-5836
212.
Childs B. G., Gluscevic M., Baker D. J., et al. Senescent cells: an emerging target for diseases of ageing. Nature Reviews. Drug Discovery. 2017;16(10):718-735.
Not in our library10.1038/nrd.2017.116
213.
Baker D. J., Childs B. G., Durik M., et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184-189.
Not in our library10.1038/nature16932
214.
Prattichizzo F., de Nigris V., la Sala L., Procopio A. D., Olivieri F., Ceriello A. “Inflammaging” as a druggable target: a senescence-associated secretory phenotype-centered view of type 2 diabetes. Oxidative Medicine and Cellular Longevity. 2016;2016:10.
Not in our library10.1155/2016/1810327
215.
Xu M., Tchkonia T., Ding H., et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proceedings of the National Academy of Sciences of the United States of America. 2015;112(46):E6301-E6310.
Not in our library10.1073/pnas.1515386112
216.
Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2 · 2015
No notice
217.
Tasdemir N., Banito A., Roe J.-S., et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discovery. 2016;6(6):612-629.
Not in our library10.1158/2159-8290.cd-16-0217
218.
Dong X., Hu X., Chen J., Hu D., Chen L. F. BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis. Cell Death & Disease. 2018;9(2):p. 203.
Not in our library10.1038/s41419-017-0181-6
219.
Zhou L., Li Y., Zhou D., Tan R. J., Liu Y. Loss of klotho contributes to kidney injury by derepression of Wnt/β-catenin signaling. Journal of the American Society of Nephrology. 2013;24(5):771-785.
Not in our library10.1681/asn.2012080865
220.
Reddy M. A., Sumanth P., Lanting L., et al. Losartan reverses permissive epigenetic changes in renal glomeruli of diabetic db/db mice. Kidney International. 2014;85(2):362-373.
Not in our library10.1038/ki.2013.387
221.
Kan W. C., Hwang J. Y., Chuang L. Y., et al. Effect of osthole on advanced glycation end products-induced renal tubular hypertrophy and role of klotho in its mechanism of action. Phytomedicine. 2019;53:205-212.
Not in our library10.1016/j.phymed.2018.09.030
222.
Mirza S. B., Ekhteiari Salmas R., Fatmi M. Q., Durdagi S. Discovery of klotho peptide antagonists against Wnt3 and Wnt3a target proteins using combination of protein engineering, protein-protein docking, peptide docking and molecular dynamics simulations. Journal of Enzyme Inhibition and Medicinal Chemistry. 2017;32(1):84-98.
Not in our library10.1080/14756366.2016.1235569
223.
Compagnucci C., Bertini E. The potential of iPSCs for the treatment of premature aging disorders. Genome Biology. 2017;18(11):p. 2350.
Not in our library10.3390/ijms18112350
224.
Villeda S. A., Plambeck K. E., Middeldorp J., et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine. 2014;20(6):659-663.
Not in our library10.1038/nm.3569
225.
Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila · 2010
No notice
226.
Eirin A., Lerman L. O. Mesenchymal stem cell treatment for chronic renal failure. Stem Cell Research & Therapy. 2014;5(4):p. 83.
Not in our library10.1186/scrt472
227.
Conboy I. M., Conboy M. J., Wagers A. J., Girma E. R., Weissman I. L., Rando T. A. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature. 2005;433(7027):760-764.
Not in our library10.1038/nature03260
228.
Villeda S. A., Luo J., Mosher K. I., et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature. 2011;477(7362):90-94.
Not in our library10.1038/nature10357
229.
Rodrigues C. E., Capcha J. M. C., de Bragança A. C., et al. Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury. Stem Cell Research & Therapy. 2017;8(1):p. 19.
Not in our library10.1186/s13287-017-0475-8
230.
Ullah M., Sun Z. Stem cells and anti-aging genes: double-edged sword-do the same job of life extension. Stem Cell Research & Therapy. 2018;9(1):p. 3.
Not in our library10.1186/s13287-017-0746-4
231.
Shi Y., Zhang Y., Tian H., et al. Improved dialytic removal of protein-bound uremic toxins by intravenous lipid emulsion in chronic kidney disease rats. Nephrology Dialysis Transplantation. 2019.
Not in our library10.1093/ndt/gfz079
232.
Madero M., Cano K. B., Campos I., et al. Removal of protein-bound uremic toxins during hemodialysis using a binding competitor. Clinical Journal of the American Society of Nephrology. 2019;14(3):394-402.
Not in our library10.2215/cjn.05240418
233.
Rossi M., Klein K., Johnson D. W., Campbell K. L. Pre-, pro-, and synbiotics: do they have a role in reducing uremic toxins? A systematic review and meta-analysis. International Journal of Nephrology. 2012;2012:20.
Not in our library10.1155/2012/673631
234.
Meijers B. K. I., de Preter V., Verbeke K., Vanrenterghem Y., Evenepoel P. p-Cresyl sulfate serum concentrations in haemodialysis patients are reduced by the prebiotic oligofructose-enriched inulin. Nephrology, Dialysis, Transplantation. 2010;25(1):219-224.
Not in our library10.1093/ndt/gfp414
235.
Ranganathan N., Ranganathan P., Friedman E. A., et al. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Advances in Therapy. 2010;27(9):634-647.
Not in our library10.1007/s12325-010-0059-9
236.
Rossi M., Johnson D. W., Morrison M., et al. Synbiotics easing renal failure by improving gut microbiology (SYNERGY): a randomized trial. Clinical Journal of the American Society of Nephrology. 2016;11(2):223-231.
Not in our library10.2215/cjn.05240515
237.
High Amylose Resistant Starch Diet Ameliorates Oxidative Stress, Inflammation, and Progression of Chronic Kidney Disease · 2014
No notice
238.
Sirich T. L., Plummer N. S., Gardner C. D., Hostetter T. H., Meyer T. W. Effect of increasing dietary fiber on plasma levels of colon-derived solutes in hemodialysis patients. Clinical Journal of the American Society of Nephrology. 2014;9(9):1603-1610.
Not in our library10.2215/cjn.00490114
239.
Han R., Li L., Ugalde A. P., et al. Functional CRISPR screen identifies AP1-associated enhancer regulating FOXF1 to modulate oncogene-induced senescence. Genome Biology. 2018;19(1):p. 118.
Not in our library10.1186/s13059-018-1494-1
240.
Liu X., Wei L., Dong Q., et al. A large-scale CRISPR screen and identification of essential genes in cellular senescence bypass. Aging. 2019;11(12):4011-4031.
Not in our library10.18632/aging.102034

Cited by papers we hold 3

Effects of Shenkang Pills on Early-Stage Diabetic Nephropathy in db/db Mice via Inhibiting AURKB/RacGAP1/RhoA Signaling Pathway · 2022
Not checked
Circular RNA in renal diseases · 2020
No notice
Role of p53 in the Regulation of Cellular Senescence · 2020
No notice

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