Notch Activation Differentially Regulates Renal Progenitors Proliferation and Differentiation Toward the Podocyte Lineage in Glomerular Disorders

Abstract

Glomerular diseases account for 90% of end-stage kidney disease. Podocyte loss is a common determining factor for the progression toward glomerulosclerosis. Mature podocytes cannot proliferate, but recent evidence suggests that they can be replaced by renal progenitors localized within the Bowman's capsule. Here, we demonstrate that Notch activation in human renal progenitors stimulates entry into the S-phase of the cell cycle and cell division, whereas its downregulation is required for differentiation toward the podocyte lineage. Indeed, a persistent activation of the Notch pathway induced podocytes to cross the G2/M checkpoint, resulting in cytoskeleton disruption and death by mitotic catastrophe. Notch expression was virtually absent in the glomeruli of healthy adult kidneys, while a strong upregulation was observed in renal progenitors and podocytes in patients affected by glomerular disorders. Accordingly, inhibition of the Notch pathway in mouse models of focal segmental glomerulosclerosis ameliorated proteinuria and reduced podocyte loss during the initial phases of glomerular injury, while inducing reduction of progenitor proliferation during the regenerative phases of glomerular injury with worsening of proteinuria and glomerulosclerosis. Taken altogether, these results suggest that the severity of glomerular disorders depends on the Notch-regulated balance between podocyte death and regeneration provided by renal progenitors.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 53

1. 1.

   Szczech LA, Lazar IL. Projecting the United States ESRD population: Issues regarding treatment of patients with ESRD. Kidney Int Suppl. 2004;90:S3-S7.

   Not in our library10.1111/j.1523-1755.2004.09002.x

2. 2.

   Kwoh C, Shannon MB, Miner JH, et al. Pathogenesis of nonimmune glomerulopathies. Annu Rev Pathol. 2006;1:349-374.

   Not in our library10.1146/annurev.pathol.1.110304.100119

3. 3.

   Wiggins RC. The spectrum of podocytopathies: A unifying view of glomerular diseases. Kidney Int. 2007;71:1205-1214.

   Not in our library10.1038/sj.ki.5002222

4. 4.

   Kriz W, Lemley KV. The role of the podocyte in glomerulosclerosis. Curr Opin Nephrol Hypertens. 1999;8:489-497.

   Not in our library10.1097/00041552-199907000-00014

5. 5.

   Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol. 2002;13:3005-3015.

   Not in our library10.1097/01.asn.0000039661.06947.fd

6. 6.

   Sagrinati C, Netti GS, Mazzinghi B, et al. Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. J Am Soc Nephrol. 2006;17:2443-2456.

   Not in our library10.1681/asn.2006010089

7. 7.

   Lazzeri E, Crescioli C, Ronconi E, et al. Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol. 2007;18:3128-3138.

   Not in our library10.1681/asn.2007020210

8. 8.

   Mazzinghi B, Ronconi E, Lazzeri E, et al. Essential but differential role for CXCR4 and CXCR7 in the therapeutic homing of human renal progenitor cells. J Exp Med. 2008;205:479-490.

   Not in our library10.1084/jem.20071903

9. 9.

   Sagrinati C, Ronconi E, Lazzeri E, et al. Stem-cell approaches for kidney repair: Choosing the right cells. Trends Mol Med. 2008;14:277-285.

   Not in our library10.1016/j.molmed.2008.05.005

10. 10.

    Ronconi E, Sagrinati C, Angelotti ML, et al. Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol. 2009;20:322-332.

    Not in our library10.1681/asn.2008070709

11. 11.

    Appel D, Kershaw D, Smeets B, et al. Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol. 2009;20:333-343.

    Not in our library10.1681/asn.2008070795

12. 12.

    Romagnani P. Toward the identification of a “renopoietic system”? Stem Cells. 2009;27:2247-2253.

    Not in our library10.1002/stem.140

13. 13.

    Smeets B, Angelotti ML, Rizzo P, et al. Renal progenitor cells contribute to hyperplastic glomerular lesions of different types of podocytopathies and in crescentic glomerulonephritis. J Am Soc Nephrol. 2009;20:2593-603.

    Not in our library10.1681/asn.2009020132

14. 14.

    Smeets B, Uhlig S, Fuss A, et al. Parietal epithelial cells are the main component of glomerular extracapillary cellular lesions. J Am Soc Nephrol. 2009;20:2604-2615.

    Not in our library10.1681/asn.2009010122

15. 15.

    Lazzeri E, Mazzinghi B, Romagnani P. Regeneration and the kidney. Curr Opin Nephrol Hypertens. 2010;19:248-253.

    Not in our library10.1097/mnh.0b013e32833680dc

16. 16.

    Lasagni L, Romagnani P. Glomerular epithelial stem cells: The good, the bad and the ugly. J Am Soc Nephrol. 2010.

    Not in our library10.1681/asn.2010010048

17. 17.

    Romagnani P. From Proteus to Prometheus: Learning from fish to modulate regeneration. J Am Soc Nephrol. 2010;21:726-728.

    Not in our library10.1681/asn.2010020228

18. 18.

    Blanpain C, Horsley V, Fuchs E. Epithelial stem cells: Turning over new leaves. Cell. 2007;128:445-458.

    Not in our library10.1016/j.cell.2007.01.014

19. 19.

    Fortini ME. Notch signalling: The core pathway and its posttranslational regulation. Dev Cell. 2009;16:633-647.

    Not in our library10.1016/j.devcel.2009.03.010

20. 20.

    Mizutani K, Yoon K, Dang L, et al. Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature. 2007;449:351-355.

    Not in our library10.1038/nature06090

21. 21.

    Carlson ME, Hsu M, Conboy IM. Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cells. Nature. 2008;454:528-532.

    Not in our library10.1038/nature07034

22. 22.

    Campa VM, Gutiérrez-Lanza R, Cerignoli F, et al. Notch activates cell cycle reentry and progression in quiescent cardiomyocytes. J Cell Biol. 2008;183:129-141.

    Not in our library10.1083/jcb.200806104

23. 23.

    Romagnani P, Annunziato F, Lasagni L, et al. Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. J Clin Invest. 2001;107:53-63.

    Not in our library10.1172/jci9775

24. 24.

    Lasagni L, Francalanci M, Annunziato F, et al. An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4. J Exp Med. 2003;197:1537-1549.

    Not in our library10.1084/jem.20021897

25. 25.

    Kita A, Imayoshi I, Hojo M, et al. Hes1 and Hes5 control the progenitor pool, intermediate lobe specification, and posterior lobe formation in the pituitary development. Mol Endocrinol. 2007;21:1458-1466.

    Not in our library10.1210/me.2007-0039

26. 26.

    Woo SM, Kim J, Han HW, et al. Notch signaling is required for maintaining stem-cell features of neuroprogenitor cells derived from human embryonic stem cells. BMC Neurosci. 2009;10:97-108.

    Not in our library10.1186/1471-2202-10-97

27. 27.

    Varnum-Finney B, Dallas MH, Kato K, et al. Notch target Hes5 ensures appropriate Notch induced T- versus B-cell choices in the thymus. Blood. 2008;111:2615-2620.

    Not in our library10.1182/blood-2007-03-079855

28. 28.

    Pippin J, Durvasula R, Petermann A, et al. DNA damage is a novel response to sublytic C5b-9-induced injury in podocytes. J Clin Invest. 2003;111:877-885.

    Not in our library10.1172/jci15645

29. 29.

    Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int. 2005;67:404-419.

    Not in our library10.1111/j.1523-1755.2005.67097.x

30. 30.

    Lee VW, Wang Y, Qin X, et al. Adriamycin nephropathy in severe combined immunodeficient (SCID) mice. Nephrol Dial Transplant. 2006;21:3293-3298.

    Not in our library10.1093/ndt/gfl413

31. 31.

    Shankland SJ, Floege J, Thomas SE, et al. Cyclin kinase inhibitors are increased during experimental membranous nephropathy: Potential role in limiting glomerular epithelial cell proliferation in vivo. Kidney Int. 1997;52:404-413.

    Not in our library10.1038/ki.1997.347

32. 32.

    Schiffer M, Bitzer M, Roberts IS, et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001;108:807-816.

    Not in our library10.1172/jci12367

33. 33.

    Schiffer M, Schiffer LE, Gupta A, et al. Inhibitory Smads and TGF-β signalling in glomerular cells. J Am Soc Nephrol. 2002;13:2657-2666.

    Not in our library10.1097/01.asn.0000033276.06451.50

34. 34.

    Kroemer G, Galluzzi L, Vandenabeele P, et al. Classification of cell death: Recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 2009;16:3-11.

    Not in our library10.1038/cdd.2008.150

35. 35.

    Vakifahmetoglu H, Olsson M, Zhivotovsky B. Death through a tragedy: Mitotic catastrophe. Cell Death Differ. 2008;15:1153-1162.

    Not in our library10.1038/cdd.2008.47

36. 36.

    Kriz W, Hähnel B, Rösener S, et al. Long-term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis. Kidney Int. 1995;48:1435-1450.

    Not in our library10.1038/ki.1995.433

37. 37.

    Nagata M, Kriz W. Glomerular damage after uninephrectomy in young rats. II. Mechanical stress on podocytes as a pathway to sclerosis. Kidney Int. 1992;42:148-160.

    Not in our library10.1038/ki.1992.272

38. 38.

    Huang XR, Holdsworth SR, Tipping PG. Evidence for delayed-type hypersensitivity mechanisms in glomerular crescent formation. Kidney Int. 1994;46:69-78.

    Not in our library10.1038/ki.1994.245

39. 39.

    Tenschert S, Elger M, Lemley KV. Glomerular hypertrophy after subtotal nephrectomy: Relationship to early glomerular injury. Virchows Arch. 1995;426:509-517.

    Not in our library10.1007/bf00193175

40. 40.

    Nagata M, Yamaguchi Y, Komatsu Y, et al. Mitosis and presence of binucleate cells among glomerular podocytes in diseased human kidneys. Nephron. 1995;70:68-71.

    Not in our library10.1159/000188546

Cited by papers we hold 3

• Kidney Decellularized Extracellular Matrix Enhanced the Vascularization and Maturation of Human Kidney Organoids · 2022
  No notice
• Podocyte Mitosis – A Catastrophe · 2012
  No notice
• The Directed Differentiation of Human iPS Cells into Kidney Podocytes · 2012
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.