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Inflammation in the pathogenesis of microvascular complications in diabetes

Dung V. Nguyen, Lynn C. Shaw, Maria B. Grant

Frontiers in Endocrinology · 2012

doi:10.3389/fendo.2012.00170

Abstract

Diabetes and hyperglycemia create a proinflammatory microenvironment that progresses to microvascular complications such as nephropathy, retinopathy, and neuropathy. Diet-induced insulin resistance is a potential initiator of this change in type 2 diabetes which can increase adipokines and generate a chronic low-grade inflammatory state. Advanced glycation end-products and its receptor, glycation end-products AGE receptor axis, reactive oxygen species, and hypoxia can also interact to worsen complications. Numerous efforts have gained way to understanding the mechanisms of these modulators and attenuation of the inflammatory response, however, effective treatments have still not emerged. The complexity of inflammatory signaling may suggest a need for multi-targeted therapy. This review presents recent findings aimed at new treatment strategies.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 23, 2026. Paragraph numbers are ours, so an answer can point at one.

INTRODUCTION

Inflammation plays an essential role in the progression of diabetic microvascular complications. Proinflammatory cytokines C-reactive protein, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 all demonstrate increased expression in diabetes. In chronic hyperglycemia, cytokines infiltrate vascular tissues and inhibit function and repair. Obesity is a major risk factor for diabetes and can induce inflammation by Toll-like receptor (TLR) activation to recruit proinflammatory cytokines and chemokines. With the onset of diabetes, adipokines such as TNF-α and IL-6 may contribute to insulin resistance. Adiponectin is initially upregulated to increase glucose uptake, and nitric oxide (NO) production; however, continued obesity may reduce adiponectin leading to complications observed in type 2 diabetes (T2D;; ). Obesity is also associated with hyperlipidemia with elevated levels of cholesterol and triglycerides which may contribute to inflammation and diabetic retinopathy (DR; ). The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found no relationship between serum lipid levels and DR. Fenofibrate is known to lower lipid levels, but it can also activate peroxisome proliferator-activated receptors (PPARs) and suppress inflammation by inhibiting nuclear factor kappa B (NF-κB; ). As metabolic syndrome and inflammation persist, oxidative stress, hypoxia, and advanced glycation end-products (AGEs)/AGE receptor (RAGE) converge to exacerbate the problem. A schematic summarizing the pathogenesis of diabetic microvascular complications is presented (Figure 1). The focus of this review is to overview the most recent findings relevant to treating nephropathy, retinopathy, and neuropathy.

DIABETIC NEPHROPATHY

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. DN results in basement membrane thickening, expansion of the mesangium, reduced filtration, albuminuria, and ultimately renal failure. Inflammatory cells can accumulate in glomeruli and interstitium to worsen DN. Recent findings have identified a few key receptors involved in renal protection. Studies targeting these pathways along with other known mediators of inflammation have revealed the importance of inflammation in worsening DN.

Peroxisome proliferator-activated receptors are activated in response to fatty acids and regulate lipid and glucose homeostasis. In the kidney, PPARγ expression has been found in medullary collecting ducts, pelvic urothelium, and isolated glomeruli and cultured mesangial cells. Pioglitazone, a PPARγ agonist, increased anti-oxidant activity and reduced inflammation in hyperoxaluric rats. This suggests activation of PPARγ may have renoprotective functions. Similarly, the same agonist treated in T2D diabetic rats showed improved insulin resistance, glycemic control, and lipid profile while reducing inflammation by reducing macrophage infiltration and NF-κB expression.

Resveratrol (trans-3,4′,5-trihydroxyestilbene, RSV) is a polyphenolic compound found in grapes and other plants providing anti-oxidant effects. RSV improved renal function and reduced oxidative stress in type 1 diabetic (T1D) rats. Similarly, RSV treatment showed significant decreases in superoxide anion and protein carbonyl oxidative stress markers. RSV was shown to reduce renal lipotoxicity and mesangial cell glucotoxicity in diabetic mice mediated through activation of PPARγ co-activator 1α. In another study, RSV reduced IL-1β in streptozotocin (STZ)-diabetic rat kidneys, but there was a significant increase in TNF-α and IL-6 levels independent of NF-κB activation, suggesting RSV has both stimulatory and inhibitory effects on cytokines simultaneously and achieving the optimal dose may be critical to establishing efficacy.

Fcγ receptors (FcγR) are present in leukocytes, glomerular, and mesangial cells. FcγR can bind to immunoglobulin G (IgG). Circulating oxidized LDL-containing immune complexes (oxLDL-IC) are increased in diabetes stimulate synthesis of IgGs in addition to other proinflammatory cytokines such as IL-1β, IL-6, IL-18, and TNF-α in Mono Mac 6 cells and primary human macrophages. Increased oxLDL-ICs also increases matrix production in mesenchymal mesangial cells through activation of FcγRI and FcγRIII to increase collagen IV production in nephropathy. Attenuating FcγR activity may reduce the development of a proinflammatory environment and enhanced matrix production. A genetic defect in FcγR attenuated diabetic renal injury based on histological analyses and reduced leukocyte accumulation in glomeruli and interstitium. There was also a reduction in intracellular superoxide generation in vivo and oxidative response to oxLDL-ICs in vitro.

Dietary lipids preceding diabetes have been shown to upregulate proinflammatory cytokines and TLR transcriptional levels along with downregulation of transcripts involved in glucose metabolism in epididymal and mesenteric white adipose tissue. TLR are innate immune receptors that have been implicated in T1D, T2D, and its associated complications. In DN, TLR4 expression was increased in T2D and uremic patients and in mouse mesangial cells, suggesting its role in monocyte recruitment. Studies confirmed increased TLR4 activation when cells were incubated with high glucose. Monocytes displaying CD14+CD16+surface markers in the kidney can associate with TLR and activate NF-κB, and STAT expression to further promote a proinflammatory microenvironment. Therapeutic targets correcting dysregulated TLR signaling may therefore be an important target against inflammation and complications within the kidney.

Advanced glycation end-product production is widely associated with diabetic microvascular complications. Recent studies showed little benefit using benfotiamine, a lipophilic thiamine-derivative that activates transketolase to reduce AGE precursors. Benfotiamine had no effect in decreasing existing plasma AGE or increasing AGE excretion. Similarly, evaluation of benfotiamine in cerebral cortex of STZ-induced diabetic rats showed little effect on reducing AGEs and TNF-α, however, it slightly attenuated oxidative stress. Despite the outcome, this approach remains active and a recent proposal has aimed at modifying the delivery to have dual targets instead of singular targeting. Using a nanoparticle shell, both AGE and RAGE inhibitors will be encased within the shell to suppress both axes and redundancy not addressed with a single therapy. The exterior of the shell will contain RAGE analogs, which can also provide specificity to AGEs and delivery of therapeutics. This dual therapy approach is still in its infancy, but it may have potential benefits if pursued to target both receptors and its ligands.

Current standard treatment of DN targets the renin–angiotensin system (RAS) through usage of angiotensin converting enzyme (ACE) inhibitors to limit systemic blood pressure to control intraglomerular pressure. Upstream targeting may further decrease RAS activity. Aliskiren, a direct renin inhibitor, has been recently evaluated in DN. Treatment using aliskiren showed a significant reduction in TNF-α and transforming growth factor (TGF)-β. Some studies have shown that TGF-β may have a role in influencing renal growth and inflammation as well as fibrosis and renal dysfunction.

DIABETIC RETINOPATHY

Diabetic retinopathy is one of the leading causes of blindness in adults of working age adults. Background DR is characterized by ischemic injury which creates a hypoxic environment in ocular tissues. Hypoxia has been shown to induce microglia activation and recruitment to ischemic sites in retinas. Vascular injury in background DR and proliferative DR (PDR) increases proinflammatory cytokines which can promote leukostasis and vascular endothelial growth factor (VEGF) mediated permeability in the retinal vasculature.

The retinal pigment epithelium (RPE) provides functional barriers for the exchange of nutrients to photoreceptor cells. Under hyperglycemia, microglia and macrophages accumulate in the RPE in Goto Kakizaki rats. Increases in transepithelial pores compromise tight junction integrity and allow materials to enter the choroidal space. Presence of inflammation can reduce transepithelial resistance (TER) and impact ion gradient generation between membrane transporters and tight junctions. TNF-α exposure to human RPE cells showed decreased TER. GPR109A is a G protein-coupled receptor (GPCR) present in RPE that is upregulated in diabetic mouse and human retina. GPR109A has immunomodulatory effects in adipose tissue and progression of atherosclerosis. Two ligands of GPR109A, niacin and β-hydroxybutyrate, was shown to suppress IL-6 and chemokine ligand-2 (CCL2) induced by TNF-α. Additional studies should explore potential value of modulating GPR109A activity with its ligands to suppress inflammation in the retina of those discussed as well as other proinflammatory cytokines.

β-catenin is a downstream effector of the Wnt pathway and is found to be increased in several diabetic rodent models and in humans. Increased β-catenin may be due to sustained Wnt signaling where it can also activate NF-κB to induce inflammation. DR is characterized by hypoxia and oxidative stress, which contribute to Wnt activation. Blockage of Wnt led to reduced inflammation through decreased ICAM-1 in the retina. Mab2F1, a monoclonal antibody targeting Wnt co-receptor LDL receptor-related protein 6 resulted in reduced retinal vascular leakage, inflammation, and attenuation of leukostasis.

Comparing cytokine levels of peripheral blood in diabetic patients revealed that levels of IL-22 expressed by T-helper (Th) 22 was significantly increased compared to controls, however, the differences were not significant between NPDR, PDR, and in diabetic patients without DR. IL-22 levels were also positively correlated with duration of diabetes. TNF-α has been shown to be increased in serum of diabetic patients. The results from this study suggest a potential role of Th22 expressing IL-22 levels in the pathogenesis of diabetic complications.

Increased RAGE levels and its ligand S100B are found in rat diabetic retinas and also found in cultured Müller glial cells exposed to high glucose. S100B has been shown induce inflammatory cytokines such as TNF-α and vascular CAM (VCAM)-1 in human microvascular endothelial cells. Similarly, Müller glial cells treated with exogenous S100B showed increased levels of TNF-α, IL-6, IL-8, VEGF, and CCL2. Treatment of S100B in cells showed a dose-dependent activation of mitogen-activated protein kinase pathway (MAPK). In vivo studies should assess the relevant concentrations of S100B in pathogenesis of DR.

The RAS plays a vital role in regulating many physiological processes of the vascular system. Elevated levels of renin, prorenin, and Angiotensin II (Ang II) are found in patients with DR. In PDR, prorenin and its receptor [(P)RR] are upregulated in retinal endothelial cells. Increased (P)RR, prorenin, and activated prorenin were found in human vitreous fluid which can promote inflammatory angiogenesis in the eye. (P)RR can activate extracellular signal-regulated kinases (ERK) and induce inflammatory responses in the eye. Blockage of (P)RR reduced ERK activity and decreased diabetes-induced retinal inflammation.

Downstream effectors also have important functions in DR. Ang II, a product of ACE, activates the AT1 receptor to induce vasoconstriction, proliferation, fibrosis, and inflammation. The protective arm of the RAS involves ACE2, which produces Ang-(1-7). As a vasodilator peptide with anti-hypertensive, anti-hypertrophic, anti-fibrotic, and anti-thrombotic functions (3), Ang-(1-7) stimulates NO production by activating endothelial NO synthase (eNOS) in an Akt-dependent manner and decreases ROS production by attenuating NADPH oxidase. Ang-(1-7) mediates its effects by activating the GPCR, the Mas receptor. Chronic Ang-(1-7) treatment preserves endothelial function in rat models of myocardial ischemia and in-stent restenosis. Treatment with ACE2 or Ang-(1-7) corrected diabetic defects in therapeutic angiogenesis (; Figure 2). Intraocular administration of adeno-associated virus expressing ACE2/Ang-(1-7) significantly reduced CD45+ macrophages, CD11b+ microglial cells, and oxidative damage in mice. Targeting both upstream and downstream components of the RAS axis may provide synergistic effects in treating microvascular complications.

DIABETIC NEUROPATHY

Diabetic neuropathy (DNO) is the most common complication of diabetes, where population-based studies have indicated more than half of the patients with either T1D or T2D develop DNO, and as much as 30% of those manifestations are painful. Recent reviews have emphasized the importance of targeting oxidative stress and inflammation in the treatment of DNO.

Tumor necrosis factor-α has been implicated in contributing to insulin resistance in obesity due to its increased expression in adipose tissue. Obese mice with a TNF-α-/-mutation displayed improved insulin sensitivity and lowered circulating fatty acids, improving obesity-induced glucose tolerance. Increased plasma TNF-α and macrophages are also associated with the progression of DNO, suggesting continued expression of these cytokines contribute to diabetic microvascular complications. Similar experiments evaluating TNF-α null mice showed that they are less susceptible to developing diabetic complications. Targeting TNF-α through pharmacological means can potentially reverse the deleterious effects in DNO. Infliximab, a monoclonal anti-TNF-α antibody approved for treatment of autoimmune diseases such as rheumatoid arthritis and psoriasis has been explored. Administration of infliximab into T1D mice showed significant improvement in neural function comparable to non-diabetic controls.

Tumor necrosis factor-α can also influence AGE/RAGE activity making it a relevant target in DNO. In the progression of DNO, RAGE expression was increased in diabetic peripheral nerves and dorsal root ganglia (DRG; ). Mice models deficient in RAGE attenuated the structural and electrophysiological changes in peripheral nerves and DRG after prolonged diabetes of 5 months and also reduced NF-κB and protein kinase C activation. NF-κB can induce apoptosis, cell cycle, and plasticity, neurogenesis, and differentiation in the central nervous system. RSV has been shown to inhibit NF-κB activity and TNF-α, IL-6, and cyclooxygenase-2 levels. BAY 11-7082, an inhibitor of kappa B (IκB) phosphorylation, downregulated NF-κB and led to improved sensory response, motor nerve conduction velocity, and nerve blood flow. Similarly, there was a significant reduction in the oxidative stress marker, malondialdehyde, IL-6, and TNF-α levels. While IL-6 is generally regarded as proinflammatory, its role in DNO is still unclear since IL-6 administration may have neurotrophic effects.

Bradykinin B1 receptor (B1R) of the kallikrein–kinin system has been shown to be upregulated in response to increases of oxidative stress in diabetes. In another study, minocycline has been shown to exhibit anti-inflammatory and anti-oxidant effects by inhibiting microglia activation. Inhibition of microglia activation in STZ-diabetic rats using either fluorocitrate or minocycline reduced B1R expression along with IL-1β and TNF-α proinflammatory cytokines in spinal dorsal horn. Microglia inhibitors may have an effect on thermal hyperalgesia and allodynia which support a role of B1R in pain neuropathy. Antagonists to B1R showed a reversal of allodynia in STZ-diabetic rats, suggesting the mediation of early DNO due to inflammation. However, in Akita mice, loss of B1R and bradykinin B2 receptor (B2R) appears to exacerbate nephropathy and neuropathy, suggesting that its activation in this diabetes model may be protective. Further studies should assess the role of B1R in different animal models of diabetes.

Angiopoietin-1 (Ang-1) has been demonstrated to have benefits against vascular leakage and endothelial cell survival. Variants have been developed to improve on solubility and potency. Matrilin-1-Ang-1 (MAT-Ang-1) has been demonstrated to have anti-inflammatory protection against cytokines IL-1α, IL-1β, IL-6, and TNF-α in sepsis. Another variant, cartilage oligomeric matrix protein (COMP)-Ang-1, has been hypothesized to improve regeneration of nerve fibers and endoneural microvessels in leptin-deficient obese (ob/ob) mice, a model for T2D. COMP-Ang-1 treatment was capable of reducing macrophage infiltration and T-cell number in sciatic nerves of ob/ob mice by 45 and 47%, respectively. Upstream effectors of Ang-1 have also recently been explored. Thymosin β4 improved diabetes-induced vascular dysfunction in sciatic nerve, nerve function and can mediate this through upregulation of Ang-1 in diabetic mice. Regulators of Ang-1 may therefore have benefits against neural and vascular dysfunction.

CONCLUSION

The worldwide increase in prevalence of obesity and diet-induced insulin resistance increases the need to reduce chronic inflammation. Diabetic microvascular complications progress due to inflammation which originates from multiple pathways and mechanisms. This complexity warrants the need for effective therapies that target more than one signaling cascade. Inhibition of both inflammatory cytokines and their activators/regulators may provide additional coverage to treating nephropathy, retinopathy, and neuropathy. Similarly, this can be combined and optimized with anti-oxidant and AGE/RAGE therapies to mitigate compensatory mechanisms. As further studies emerge to address current limitations, improved therapies targeting diabetic microvascular complications may ultimately transition from treating the pathology to prevention.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 103

  1. 1.

    Abdelsamie S. A. Li Y. Huang Y. Lee M. H. Klein R. L. Virella G. (2011 ). Oxidized LDL immune complexes stimulate collagen IV production in mesangial cells via Fc gamma receptors I and III. Clin. Immunol. 139 258–266

    Not in our library10.1016/j.clim.2011.01.016

  2. 2.

    Alfieri A. Watson J. J. Kammerer R. A. Tasab M. Progias P. Reeves K. (2012 ). Angiopoietin-1 variant reduces LPS-induced microvascular dysfunction in a murine model of sepsis. Crit. Care 16 R182

    Not in our library10.1186/cc11666

  3. 3.

    Alkhalaf A. Kleefstra N. Groenier K. H. Bilo H. J. G. Gans R. O. B. Heeringa P. (2012 ). Effect of benfotiamine on advanced glycation endproducts and markers of endothelial dysfunction and inflammation in diabetic nephropathy. PLoS ONE 7:e40427

    Not in our library10.1371/journal.pone.0040427

  4. 4.

    Asano T. Wakisaka M. Yoshinari M. Iino K. Sonoki K. Iwase M. (2000 ). Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation. Biochim. Biophys. Acta 1497 148–154

    Not in our library10.1016/s0167-4889(00)00054-9

  5. 5.

    Babaei-Jadidi R. Karachalias N. Ahmed N. Battah S. Thornalley P. J. (2003 ). Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 52 2110–2120

    Not in our library10.2337/diabetes.52.8.2110

  6. 6.

    Benter I. F. Yousif M. H. Dhaunsi G. S. Kaur J. Chappell M. C. Diz D. I. (2008 ). Angiotensin-(1-7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am. J. Nephrol. 28 25–33

    Not in our library10.1159/000108758

  7. 7.

    Berg A. H. Combs T. P. Du X. Brownlee M. Scherer P. E. (2001 ). The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7 947–953

    Not in our library10.1038/90992

  8. 8.

    Bonegio R. Susztak K. (2012 ). Notch signaling in diabetic nephropathy. Exp. Cell Res. 318 986–992

    Not in our library10.1016/j.yexcr.2012.02.036

  9. 9.

    Brownlee M. (2005 ). The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54 1615–1625

    Not in our library10.2337/diabetes.54.6.1615

  10. 10.

    Chang C. C. Chang C. Y. Wu Y. T. Huang J. P. Yen T. H. Hung L. M. (2011 ). Resveratrol retards progression of diabetic nephropathy through modulations of oxidative stress, proinflammatory cytokines, and AMP-activated protein kinase. J. Biomed. Sci. 18 47

    Not in our library10.1186/1423-0127-18-47

  11. 11.

    Chen H. Wen F. Zhang X. Su S. B. (2012 ). Expression of T-helper-associated cytokines in patients with type 2 diabetes mellitus with retinopathy. Mol. Vis. 18 219–226

    Not in our library

  12. 12.

    Chen Y. Hu Y. Zhou T. Zhou K. K. Mott R. Wu M. (2009 ). Activation of the Wnt pathway plays a pathogenic role in diabetic retinopathy in humans and animal models. Am. J. Pathol. 175 2676–2685

    Not in our library10.2353/ajpath.2009.080945

  13. 13.

    Chew E. Y. Ambrosius W. T. Davis M. D. Danis R. P. Gangaputra S. Greven C. M. (2010 ). Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med. 363 233–244

    Not in our library10.1056/nejmoa1001288

  14. 14.

    Chistiakov D. A. (2011 ). Diabetic retinopathy: pathogenic mechanisms and current treatments. Diabetes Metab. Syndr. 5 165–172

    Not in our library10.1016/j.dsx.2012.02.025

  15. 15.

    Cho C. H. Kammerer R. A. Lee H. J. Steinmetz M. O. Ryu Y. S. Lee S. H. (2004 ). COMP-Ang1: a designed angiopoietin-1 variant with nonleaky angiogenic activity. Proc. Natl. Acad. Sci. U.S.A. 101 5547–5552

    Not in our library10.1073/pnas.0307574101

  16. 16.

    Cotter M. A. Gibson T. M. Nangle M. R. Cameron N. E. (2010 ). Effects of interleukin-6 treatment on neurovascular function, nerve perfusion and vascular endothelium in diabetic rats. Diabetes Obes. Metab. 12 689–699

    Not in our library10.1111/j.1463-1326.2010.01221.x

  17. 17.

    Dale T. C. (1998 ). Signal transduction by the Wnt family of ligands. Biochem. J. 329(Pt2) 209–223

    Not in our library10.1042/bj3290209

  18. 18.

    de Kleijn D. Pasterkamp G. (2003 ). Toll-like Receptors in Cardiovascular Diseases. Cardiovasc. Res. 60 58–67

    Not in our library10.1016/s0008-6363(03)00348-1

  19. 19.

    Dhaunsi G. S. Bitar M. S. (2012 ). Antioxidants attenuate diabetes-induced activation of peroxisomal functions in the rat kidney. J. Biomed. Sci. 11 566–570

    Not in our library10.1159/000079667

  20. 20.

    Dias J. P. Talbot S. Sénécal J. Carayon P. Couture R. (2010 ). Kinin B1 receptor enhances the oxidative stress in a rat model of insulin resistance: outcome in hypertension, allodynia and metabolic complications. PLoS ONE 5:e12622

    Not in our library10.1371/journal.pone.0012622

  21. 21.

    Digby J. E. McNeill E. Dyar O. J. Lam V. Greaves D. R. Choudhury R. P. (2010 ). Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin. Atherosclerosis 209 89–95

    Not in our library10.1016/j.atherosclerosis.2009.08.045

  22. 22.

    Dodson P. M. Galton D. J. Winder A.F. (1981 ). Retinal vascular abnormalities in the hyperlipidaemias. Trans. Ophthalmol. Soc. U.K. 101 17–21

    Not in our library

  23. 23.

    Farmer K. L. Li C. Dobrowsky R. T. (2012 ). Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach? Pharmacol. Rev. 64 880–900

    Not in our library10.1124/pr.111.005314

  24. 24.

    Festa A. D’Agostino R. Jr. Howard G. Mykkänen L. Tracy R. P. Haffner S. M. (2000 ). Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation 102 42–47

    Not in our library10.1161/01.cir.102.1.42

  25. 25.

    Foehr E. D. Lin X. O’Mahony A. Geleziunas R. Bradshaw R. A. Greene W. C. (2000 ). NF-kappa B signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells. J. Neurosci. 20 7556–7563

    Not in our library10.1523/jneurosci.20-20-07556.2000

  26. 26.

    Ford E. S. (1999 ). Body mass index, diabetes, and C-reactive protein among U.S. adults. Diabetes Care 22 1971–1977

    Not in our library10.2337/diacare.22.12.1971

  27. 27.

    Fraser C. C. (2006 ). Exploring the positive and negative consequences of NF-kappaB inhibition for the treatment of human disease. Cell Cycle 5 1160–1163

    Not in our library10.4161/cc.5.11.2773

  28. 28.

    Gambhir D. Ananth S. Veeranan-Karmegam R. Elangovan S. Hester S. Jennings E. (2012 ). GPR109A as an anti-inflammatory receptor in retinal pigment epithelial cells and its relevance to diabetic retinopathy. Invest.Ophthalmol. Vis. Sci. 53 2208–2217

    Not in our library10.1167/iovs.11-8447

  29. 29.

    Gandhi S. Srinivasan B. Akarte A. S. (2012 ). Aliskiren improves insulin resistance and ameliorates diabetic renal vascular complications in STZ-induced diabetic rats. J. Renin Angiotensin Aldosterone Syst.

    Not in our library

  30. 30.

    Gao X. Belmadani S. Picchi A. Xu X. Potter B. J. Tewari-Singh N. (2007 ). Tumor necrosis factor-alpha induces endothelial dysfunction in Lepr(db) mice. Circulation 115 245–254

    Not in our library10.1161/circulationaha.106.650671

  31. 31.

    Gómez-Guerrero C. López-Armada M. J. González E. Egido J. (1994 ). Soluble IgA and IgG aggregates are catabolized by cultured rat mesangial cells and induce production of TNF-alpha and IL-6, and proliferation. J. Immunol. 153 5247–5255

    Not in our library

  32. 32.

    Gómez-Guerrero C. López-Franco O. Suzuki Y. Sanjuán G. Hernández-Vargas P. Blanco J. (2002 ). Nitric oxide production in renal cells by immune complexes: role of kinases and nuclear factor-kappaB. Kidney Int. 62 2022–2034

    Not in our library10.1046/j.1523-1755.2002.00653.x

  33. 33.

    Graves D. T. Kayal R. A. (2008 ). Diabetic complications and dysregulated innate immunity. Front. Biosci. 13 1227–1239

    Not in our library10.2741/2757

  34. 34.

    Harati Y. (2007 ). Diabetic neuropathies: unanswered questions. Neurol. Clin. 25 303–317

    Not in our library10.1016/j.ncl.2007.01.002

  35. 35.

    Iwashima Y. Eto M. Horiuchi S. Sano H. (1999 ). Advanced glycation end product-induced peroxisome proliferator-activated receptor gamma gene expression in the cultured mesangial cells. Biochem. Biophys. Res. Commun. 264 441–448

    Not in our library10.1006/bbrc.1999.1539

  36. 36.

    Kakoki M. Sullivan K. A. Backus C. Hayes J. M. Oh S. S. Hua K. (2010 ). Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice. Proc. Natl. Acad. Sci. U.S.A. 107 10190–10195

    Not in our library10.1073/pnas.1005144107

  37. 37.

    Kanda A. Noda K. Saito W. Ishida S. (2012 ). (Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy. Diabetologia 55 3104–3113

    Not in our library10.1007/s00125-012-2702-2

  38. 38.

    Karachalias N. Babaei-Jadidi R. Rabbani N. Thornalley P. J. (2010 ). Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia 53 1506–1516

    Not in our library10.1007/s00125-010-1722-z

  39. 39.

    Kaur H. Chien A. Jialal I. (2012 ). Hyperglycemia induces Toll like receptor 4 expression and activity in mouse mesangial cells: relevance to diabetic nephropathy. Am. J. Physiol. Renal Physiol. 303 F1145–F1150

    Not in our library10.1152/ajprenal.00319.2012

  40. 40.

    Keech A. C. Mitchell P. Summanen P. A. O’Day J. Davis T. M. Moffitt M. S. (2007 ). Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370 1687–1697

    Not in our library10.1016/s0140-6736(07)61607-9

  41. 41.

    Kielczewski J. L. Hu P. Shaw L. C. Li Calzi S. Mames R. N. Gardiner T. A. (2011 ). Novel protective properties of IGFBP-3 result in enhanced pericyte ensheathment, reduced microglial activation, increased microglial apoptosis, and neuronal protection after ischemic retinal injury. Am. J. Pathol. 178 1517–1528

    Not in our library10.1016/j.ajpath.2010.12.031

  42. 42.

    Kim M. Y. Lim J. H. Youn H. H. Hong Y. A. Yang K. S. Park H. S. (2012 ). Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice. Diabetologia

    Not in our library

  43. 43.

    Ko G. J. Kang Y. S. Han S. Y. Lee M. H. Song H. K. Han K. H. (2008 ). Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. Nephrol. Dial. Transplant. 23 2750–2760

    Not in our library10.1093/ndt/gfn157

  44. 44.

    Kosacka J. Nowicki M. Klöting N. Kern M. Stumvoll M. Bechmann I. (2012 ). COMP-angiopoietin-1 recovers molecular biomarkers of neuropathy and improves vascularisation in sciatic nerve of ob/ob mice. PLoS ONE 7:e32881.

    Not in our library10.1371/journal.pone.0032881

  45. 45.

    Kumar A. Negi G. Sharma S. S. (2012 ). Suppression of NF-κ B and NF-κ B regulated oxidative stress and neuroinflammation by BAY 11-7082 (Iκ B phosphorylation inhibitor) in experimental diabetic neuropathy. Biochimie 94 1158–1165

    Not in our library10.1016/j.biochi.2012.01.023

  46. 46.

    Kumar A. Sharma S. S. (2010 ). NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem. Biophys. Res. Commun. 394 360–365

    Not in our library10.1016/j.bbrc.2010.03.014

  47. 47.

    Kumar A. Takada Y. Boriek A. M. Aggarwal B. B. (2004 ). Nuclear factor-kappaB: its role in health and disease. J. Mol. Med. 82 434–448

    Not in our library10.1007/s00109-004-0555-y

  48. 48.

    Kume S. Uzu T. Isshiki K. Koya D. (2008 ). Peroxisome proliferator-activated receptors in diabetic nephropathy. PPAR Res. 2008 879523

    Not in our library10.1155/2008/879523

  49. 49.

    Kwon E. Y. Shin S. K. Cho Y. Y. Jung U. J. Kim E. Park T. (2012 ). Time-course microarrays reveal early activation of the immune transcriptome and adipokine dysregulation leads to fibrosis in visceral adipose depots during diet-induced obesity. BMC Genomics 13:450

    Not in our library10.1186/1471-2164-13-450

  50. 50.

    Lang K. S. Recher M. Junt T. Navarini A. A. Harris N. L. Freigang S. (2005 ). Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease. Nat. Med. 11 138–145

    Not in our library10.1038/nm1176

  51. 51.

    Langeveld B. van Gilst W. H. Tio R. A. Zijlstra F. Roks A. J. (2005 ). Angiotensin-(1-7) attenuates neointimal formation after stent implantation in the rat. Hypertension 45 138–141

    Not in our library10.1161/01.hyp.0000149382.83973.c2

  52. 52.

    Lee K. Hu Y. Ding L. Chen Y. Takahashi Y. Mott R. (2012 ). Therapeutic potential of a monoclonal antibody blocking the wnt pathway in diabetic retinopathy. Diabetes 61 2948–2957

    Not in our library10.2337/db11-0300

  53. 53.
    Inflammation in Diabetic Nephropathy · 2012
    No notice
  54. 54.

    Limb G. A. Salt T. E. Munro P. M. Moss S. E. Khaw P. T. (2002 ). In vitro characterization of a spontaneously immortalized human Müller cell line (MIO-M1). Invest. Ophthalmol. Vis. Sci. 43 864–869

    Not in our library

  55. 55.

    Lin J. Ziring D. Desai S. Kim S. Wong M. Korin Y. (2008 ). TNFalpha blockade in human diseases: an overview of efficacy and safety. Clin. Immunol. 126 13–30

    Not in our library10.1016/j.clim.2007.08.012

  56. 56.

    Loot A. E. Roks A. J. Henning R. H. Tio R. A. Suurmeijer A. J. Boomsma F. (2002 ). Angiotensin-(1-7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 105 1548–1550

    Not in our library10.1161/01.cir.0000013847.07035.b9

  57. 57.

    Lopez-Parra V. Mallavia B. Lopez-Franco O. Ortiz-Muñoz G. Oguiza A. Recio C. (2012 ). Fcγ receptor deficiency attenuates diabetic nephropathy. J. Am. Soc. Nephrol. 23 1518–1527

    Not in our library10.1681/asn.2011080822

  58. 58.

    Lukasova M. Malaval C. Gille A. Kero J. Offermanns S. (2011 ). Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J. Clin. Invest. 121 1163–1173

    Not in our library10.1172/jci41651

  59. 59.

    Matsuzawa Y. (2005 ). Adiponectin: identification, physiology and clinical relevance in metabolic and vascular disease. Atheroscler. Suppl. 6 7–14

    Not in our library10.1016/j.atherosclerosissup.2005.02.003

  60. 60.

    Montecucco F. Quercioli A. Dallegri F. Viviani G. L. Mach F. (2010 ). New evidence for nicotinic acid treatment to reduce atherosclerosis. Expert Rev. Cardiovasc. Ther. 8 1457–1467

    Not in our library10.1586/erc.10.116

  61. 61.

    Müller S. Martin S. Koenig W. Hanifi-Moghaddam P. Rathmann W. Haastert B. (2002 ). Impaired glucose tolerance is associated with increased serum concentrations of interleukin 6 and co-regulated acute-phase proteins but not TNF-alpha or its receptors. Diabetologia 45 805–812

    Not in our library10.1007/s00125-002-0829-2

  62. 62.

    Nilsson J. Bengtsson E. Fredrikson G. N Björkbacka H. (2008 ). Inflammation and immunity in diabetic vascular complications. Curr. Opin. Lipidol. 19 519–524

    Not in our library10.1097/mol.0b013e32830f47cd

  63. 63.

    Omri S. Behar-Cohen F. de Kozak Y. Sennlaub F. Verissimo L. M. Jonet L. (2011 ). Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCζ in the Goto Kakizaki rat model. Am. J. Pathol. 179 942–953

    Not in our library10.1016/j.ajpath.2011.04.018

  64. 64.

    Oudit G. Y. Liu G. C. Zhong J. Basu R. Chow F. L. Zhou J. (2010 ). Human recombinant ACE2 reduces the progression of diabetic nephropathy. Diabetes 59 529–538

    Not in our library10.2337/db09-1218

  65. 65.

    Pabreja K. Dua K. Sharma S. Padi S. S. Kulkarni S. K. (2011 ). Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms. Eur. J. Pharmacol. 661 15–21

    Not in our library10.1016/j.ejphar.2011.04.014

  66. 66.

    Park Y. Park S. Yoo E. Kim D. Shin H. (2004 ). Association of the polymorphism for Toll-like receptor 2 with type 1 diabetes susceptibility. Ann. N. Y. Acad. Sci. 1037 170–174

    Not in our library10.1196/annals.1337.028

  67. 67.

    Peng S. Gan G. Rao V. S. Adelman R. A. Rizzolo L. J. (2012 ). Effects of proinflammatory cytokines on the claudin-19 rich tight junctions of human retinal pigment epithelium. Invest. Ophthalmol. Vis. Sci. 53 5016–5028

    Not in our library10.1167/iovs.11-8311

  68. 68.

    Peters M. A. Burke J. M. Clowry M. Abrams G. W. Williams G. A. (1986 ). Development of traction retinal detachments following intravitreal injections of retinal Muller and pigment epithelial cells. Graefes Arch. Clin. Exp. Ophthalmol. 224 554–563

    Not in our library10.1007/bf02154745

  69. 69.

    Phillips A. O. Steadman R. (2002 ). Diabetic nephropathy: the central role of renal proximal tubular cells in tubulointerstitial injury. Histol. Histopathol. 17 247–252

    Not in our library10.14670/hh-17.247

  70. 70.

    Purwata T. E. (2011 ). High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. J. Pain Res. 4 169–175

    Not in our library10.2147/jpr.s21751

  71. 71.

    Radeke H. H. Janssen-Graalfs I. Sowa E. N. Chouchakova N. Skokowa J. Löscher F. (2002 ). Opposite regulation of type II and III receptors for immunoglobulin G in mouse glomerular mesangial cells and in the induction of anti-glomerular basement membrane (GBM) nephritis. J. Biol. Chem. 277 27535–27544

    Not in our library10.1074/jbc.m200419200

  72. 72.

    Rajala M. W. Scherer P. E. (2003 ).Minireview: the adipocyte–at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144 3765–3773

    Not in our library10.1210/en.2003-0580

  73. 73.

    Ramos K. M. Jiang Y. Svensson C. I. Calcutt N. A. (2007 ). Pathogenesis of spinally mediated hyperalgesia in diabetes. Diabetes 56 1569–1576

    Not in our library10.2337/db06-1269

  74. 74.

    Rizzolo L. J. Peng S. Luo Y. Xiao W. (2011 ). Integration of tight junctions and claudins with the barrier functions of the retinal pigment epithelium. Prog. Retin. Eye Res. 30 296–323

    Not in our library10.1016/j.preteyeres.2011.06.002

  75. 75.

    Rudofsky G. Jr. Reismann P. Witte S. Humpert P. M. Isermann B. Chavakis T. (2004 ). Asp299Gly and Thr399Ile genotypes of the TLR4 gene are associated with a reduced prevalence of diabetic neuropathy in patients with type 2 diabetes. Diabetes Care 27 179–183

    Not in our library10.2337/diacare.27.1.179

  76. 76.

    Saad A. F. Virella G. Chassereau C. Boackle R. J. Lopes-Virella M. F. (2006 ). OxLDL immune complexes activate complement and induce cytokine production by MonoMac 6 cells and human macrophages. J. Lipid Res. 47 1975–1983

    Not in our library10.1194/jlr.m600064-jlr200

  77. 77.

    Sampaio W. O. Souza dos Santos R. A. Faria-Silva R. da Mata Machado L. T. Schiffrin E. L. Touyz R. M. (2007 ). Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension 49 185–192

    Not in our library10.1161/01.hyp.0000251865.35728.2f

  78. 78.

    Satofuka S. Ichihara A. Nagai N. Noda K. Ozawa Y. Fukamizu A. (2008 ). (Pro)renin receptor promotes choroidal neovascularization by activating its signal transduction and tissue renin–angiotensin system. Am. J. Pathol. 173 1911–1918

    Not in our library10.2353/ajpath.2008.080457

  79. 79.

    Satofuka S. Kanda A. Ishida S. (2012 ). Receptor-associated prorenin system in the pathogenesis of retinal diseases. Front. Biosci. 4 1449–1460

    Not in our library10.2741/s345

  80. 80.

    Sharma S. Anjaneyulu M. Kulkarni S. K. Chopra K. (2006 ). Resveratrol, a polyphenolic phytoalexin, attenuates diabetic nephropathy in rats. Pharmacology 76 69–75

    Not in our library10.1159/000089720

  81. 81.

    Suganami T. Nishida J. Ogawa Y. (2005 ). A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler. Thromb. Vasc. Biol. 25 2062–2068

    Not in our library10.1161/01.atv.0000183883.72263.13

  82. 82.

    Taguchi K. Okada A. Yasui T. Kobayashi T. Ando R. Tozawa K. (2012 ). Pioglitazone, a peroxisome proliferator activated receptor gamma agonist, decreases renal crystal deposition, oxidative stress and inflammation in hyperoxaluric rats. J. Urol. 188 1002–1011

    Not in our library10.1016/j.juro.2012.04.103

  83. 83.

    Talbot S. Chahmi E. Dias J. P. Couture R. (2010 ). Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy. J. Neuroinflammation 7 36

    Not in our library10.1186/1742-2094-7-36

  84. 84.

    Temelkova-Kurktschiev T. Henkel E. Koehler C. Karrei K. Hanefeld M. (2002 ). Subclinical inflammation in newly detected Type II diabetes and impaired glucose tolerance. Diabetologia 45 151

    Not in our library10.1007/s125-002-8256-1

  85. 85.

    Tomizawa A. Hattori Y. Inoue T. Hattori S. Kasai K. (2011 ). Fenofibrate suppresses microvascular inflammation and apoptosis through adenosine monophosphate-activated protein kinase activation. Metab. Clin. Exp. 60 513–522

    Not in our library10.1016/j.metabol.2010.04.020

  86. 86.

    Toth C. Rong L. L. Yang C. Martinez J. Song F. Ramji N. (2008 ). Receptor for advanced glycation end products (RAGEs) and experimental diabetic neuropathy. Diabetes 57 1002–1017

    Not in our library10.2337/db07-0339

  87. 87.

    Uysal K. T. Wiesbrock S. M. Marino M. W. Hotamisligil G. S. (1997 ). Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389 610–614

    Not in our library10.1038/39335

  88. 88.

    Valencia J. V. Mone M. Koehne C. Rediske J. Hughes T. E. (2004 ). Binding of receptor for advanced glycation end products (RAGE) ligands is not sufficient to induce inflammatory signals: lack of activity of endotoxin-free albumin-derived advanced glycation end products. Diabetologia 47 844–852

    Not in our library10.1007/s00125-004-1392-9

  89. 89.

    Verma A. Shan Z. Lei B. Yuan L. Liu X. Nakagawa T. (2012 ). ACE2 and Ang-(1-7) confer protection against development of diabetic retinopathy. Mol. Ther. 20 28–36

    Not in our library10.1038/mt.2011.155

  90. 90.

    Vincent A. M. Callaghan B. C. Smith A. L. Feldman E. L. (2011 ). Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat. Rev. Neurol. 7 573–583

    Not in our library10.1038/nrneurol.2011.137

  91. 91.

    Wahli W. Michalik L. (2012 ). PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab. 23 51–63

    Not in our library10.1016/j.tem.2012.05.001

  92. 92.

    Wang L. Chopp M. Szalad A. Liu Z. Lu M. Zhang L. (2012 ). Thymosin β 4 promotes the recovery of peripheral neuropathy in type II diabetic mice. Neurobiol. Dis. 48 546–555

    Not in our library10.1016/j.nbd.2012.08.002

  93. 93.

    Wen L. Peng J. Li Z. Wong F. S. (2004 ). The effect of innate immunity on autoimmune diabetes and the expression of Toll-like receptors on pancreatic islets. J. Immunol. 172 3173–3180

    Not in our library10.4049/jimmunol.172.5.3173

  94. 94.

    Wilkinson-Berka J. L. (2008 ). Prorenin and the (pro)renin receptor in ocular pathology. Am. J. Pathol. 173 1591–1594

    Not in our library10.2353/ajpath.2008.080757

  95. 95.

    Wu S. Ren J. (2006 ). Benfotiamine alleviates diabetes-induced cerebral oxidative damage independent of advanced glycation end-product, tissue factor and TNF-alpha. Neurosci. Lett. 394 158–162

    Not in our library10.1016/j.neulet.2005.10.022

  96. 96.

    Yamakawa I. Kojima H. Terashima T. Katagi M. Oi J. Urabe H. (2011 ). Inactivation of TNF-α ameliorates diabetic neuropathy in mice. Am. J. Physiol. Endocrinol. Metab. 301 E844–E852

    Not in our library10.1152/ajpendo.00029.2011

  97. 97.

    Yamashina K. Yamamoto H. Chayama K. Nakajima K. Kikuchi A. (2006 ). Suppression of STAT3 activity by Duplin, which is a negative regulator of the Wnt signal. J. Biochem. 139 305–314

    Not in our library10.1093/jb/mvj033

  98. 98.

    Yan S. Zhou C. Zhang W. Zhang G. Zhao X. Yang S. (2008 ). beta-Catenin/TCF pathway upregulates STAT3 expression in human esophageal squamous cell carcinoma. Cancer Lett. 271 85–97

    Not in our library10.1016/j.canlet.2008.05.035

  99. 99.

    Yang M. Gan H. Shen Q. Tang W. Du X. Chen D. (2012 ). Proinflammatory CD14+CD16+ monocytes are associated with microinflammation in patients with type 2 diabetes mellitus and diabetic nephropathy uremia. Inflammation 35 388–396

    Not in our library10.1007/s10753-011-9374-9

  100. 100.

    Yang T. Michele D. E. Park J. Smart A. M. Lin Z. Brosius F. C. III (1999 ). Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney. Am. J. Physiol. 277 F966–F973

    Not in our library10.1152/ajprenal.1999.277.6.f966

  101. 101.

    Zhou X. Wang B. Zhu L. Hao S. (2012 ). A novel improved therapy strategy for diabetic nephropathy: targeting AGEs. Organogenesis 8 18–21

    Not in our library10.4161/org.19332

  102. 102.
    Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-β antibody in db/db diabetic mice · 2000
    Not checked
  103. 103.

    Zong H. Ward M. Madden A. Yong P. H. Limb G. A. Curtis T. M. (2010 ). Hyperglycaemia-induced pro-inflammatory responses by retinal Müller glia are regulated by the receptor for advanced glycation end-products (RAGE). Diabetologia 53 2656–2666

    Not in our library10.1007/s00125-010-1900-z

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