Podocytes: the Weakest Link in Diabetic Kidney Disease?

Current Diabetes Reports

Volumn 16, Issue 5, 2016, Pages

  Lin, Jamie S ^a   Susztak, Katalin ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Albuminuria; Diabetes; Glomerulosclerosis; Notch; Podocytes

Indexed keywords

ADVANCED GLYCATION END PRODUCT; ADVANCED GLYCATION END PRODUCT RECEPTOR; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; NEPHRIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN A; VERY LATE ACTIVATION ANTIGEN 3;

ALBUMINURIA; CELL ADHESION; CELL DEATH; CELL DEDIFFERENTIATION; CELL FUNCTION; DIABETIC NEPHROPATHY; DISEASE DURATION; DISEASE PREDISPOSITION; GLOMERULOSCLEROSIS; GLOMERULUS BASEMENT MEMBRANE; HUMAN; HYPERGLYCEMIA; HYPERTROPHY; NONHUMAN; PATHOGENESIS; PODOCYTE; PROTEIN EXPRESSION; PROTEIN FUNCTION; RECEPTOR BINDING; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; ADAPTATION; ANIMAL; CHRONIC KIDNEY FAILURE; DISEASE COURSE; METABOLISM;

ADAPTATION, PHYSIOLOGICAL; ANIMALS; DIABETIC NEPHROPATHIES; DISEASE PROGRESSION; HUMANS; KIDNEY FAILURE, CHRONIC; PODOCYTES; RHO GTP-BINDING PROTEINS;

EID: 84962774641     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-016-0735-5     Document Type: Review

References (97)

1. Molitch ME et al. Nephropathy in diabetes. Diabetes Care. 2004;27 Suppl 1:S79–83.
2. Reddy GR et al. The podocyte and diabetes mellitus: is the podocyte the key to the origins of diabetic nephropathy? Curr Opin Nephrol Hypertens. 2008;17(1):32–6.
3. U.S. Renal Data System. USRDS 2014 annual data report: atlas of end-stage renal disease in the United States 2015.
4. Incidence of end-stage renal disease attributed to diabetes among persons with diagnosed diabetes—United States and Puerto Rico, 1996–2007. MMWR Morb Mortal Wkly Rep, 2010. 59(42): p. 1361–6.
5. Zhang L et al. Prevalence and factors associated with CKD: a population study from Beijing. Am J Kidney Dis. 2008;51(3):373–84.
6. Haroun MK et al. Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol. 2003;14(11):2934–41.
7. Lu JL et al. Association of age and BMI with kidney function and mortality: a cohort study. Lancet Diabetes Endocrinol. 2015;3(9):704–14.
8. Brancati FL et al. Risk of end-stage renal disease in diabetes mellitus: a prospective cohort study of men screened for MRFIT. Multiple risk factor intervention trial. Jama. 1997;278(23):2069–74.
9. Cruickshanks KJ et al. The association of microalbuminuria with diabetic retinopathy. The Wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology. 1993;100(6):862–7.
10. Chavers BM et al. Relationship between retinal and glomerular lesions in IDDM patients. Diabetes. 1994;43(3):441–6.
11. Klein R et al. The relationship of diabetic retinopathy to preclinical diabetic glomerulopathy lesions in type 1 diabetic patients: the renin-angiotensin system study. Diabetes. 2005;54(2):527–33.
12. Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulin-dependent diabetes mellitus. A systematic overview of the literature. Arch Intern Med. 1997;157(13):1413–8.
13. Parving HH et al. Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion. Acta Endocrinol (Copenh). 1982;100(4):550–5.
14. Mauer SM et al. Structural-functional relationships in diabetic nephropathy. J Clin Invest. 1984;74(4):1143–55.
15. Drummond K, Mauer M. The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes. 2002;51(5):1580–7.
16. Gilbert RE, Cooper ME. The tubulointerstitium in progressive diabetic kidney disease: more than an aftermath of glomerular injury? Kidney Int. 1999;56(5):1627–37.
17. Ponchiardi C, Mauer M, Najafian B. Temporal profile of diabetic nephropathy pathologic changes. Curr Diab Rep. 2013;13(4):592–9. This study describes the natural history of diabetic kidney lesions.
18. Tan AL, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol. 2007;27(2):130–43.
19. Leehey DJ et al. Role of angiotensin II in diabetic nephropathy. Kidney Int Suppl. 2000;77:S93–8.
20. Lewis EJ et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456–62.
21. Lewis EJ et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–60.
22. Veron D et al. Podocyte vascular endothelial growth factor (Vegf(1)(6)(4)) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia. 2011;54(5):1227–41.
23. Weil EJ et al. Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int. 2012;82(9):1010–7.
24. Sugimoto H et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J Biol Chem. 2003;278(15):12605–8.
25. Yamamoto T et al. Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A. 1993;90(5):1814–8.
26. Fujimoto M et al. Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. Biochem Biophys Res Commun. 2003;305(4):1002–7.
27. Iglesias-de la Cruz MC et al. Effects of high glucose and TGF-beta1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int. 2002;62(3):901–13.
28. Hathaway CK et al. Low TGFbeta1 expression prevents and high expression exacerbates diabetic nephropathy in mice. Proc Natl Acad Sci U S A. 2015;112(18):5815–20. This study suggests that blocking or decreasing TGFbeta1 might be of therapeutic value in diabetic kidney disease.
29. Osterby R. Early phases in the development of diabetic glomerulopathy. Acta Med Scand Suppl. 1974;574:3–82.
30. Mason RM, Wahab NA. Extracellular matrix metabolism in diabetic nephropathy. J Am Soc Nephrol. 2003;14(5):1358–73.
31. Gambara V et al. Heterogeneous nature of renal lesions in type II diabetes. J Am Soc Nephrol. 1993;3(8):1458–66.
32. Gunwar S et al. Glomerular basement membrane. Identification of a novel disulfide-cross-linked network of alpha3, alpha4, and alpha5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem. 1998;273(15):8767–75.
33. Zeisberg M et al. Differential expression of type IV collagen isoforms in rat glomerular endothelial and mesangial cells. Biochem Biophys Res Commun. 2002;295(2):401–7.
34. Yagame M et al. Differential distribution of type IV collagen chains in patients with diabetic nephropathy in non-insulin-dependent diabetes mellitus. Nephron. 1995;70(1):42–8.
35. Ziyadeh FN et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A. 2000;97(14):8015–20.
36. Chen S et al. Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-beta and VEGF signalling: implications for diabetic glomerulopathy. Nephrol Dial Transplant. 2005;20(7):1320–8.
37. Bai Y et al. High ambient glucose levels modulates the production of MMP-9 and alpha5(IV) collagen by cultured podocytes. Cell Physiol Biochem. 2006;17(1–2):57–68.
38. Caramori ML, Parks A, Mauer M. Renal lesions predict progression of diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol. 2013;24(7):1175–81. This study showed that GBM thickness might be able to predict which T1DM patient will develop proteinuria and ESRD.
39. Pagtalunan ME et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997;99(2):342–8.
40. Wiggins JE et al. Podocyte hypertrophy, “adaptation,” and “decompensation” associated with glomerular enlargement and glomerulosclerosis in the aging rat: prevention by calorie restriction. J Am Soc Nephrol. 2005;16(10):2953–66.
41. Wharram BL et al. Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol. 2005;16(10):2941–52.
42. Pavenstadt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83(1):253–307.
43. Huber TB, Benzing T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005;14(3):211–6.
44. Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol. 2002;13(12):3005–15.
45. Li X et al. Nephrin preserves podocyte viability and glomerular structure and function in adult kidneys. J Am Soc Nephrol. 2015;26(10):2361–77. Inducible RNAi-mediated nephrin knockdown mice showed that short versus long-term nephrin knockdown resulted in different histological outcomes when subjected to glomerular injury models. AKT phosphorylation was decreased in both short- and long-term nephrin knockdown mice.
46. Beltcheva O et al. Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. Hum Mutat. 2001;17(5):368–73.
47. Simons M et al. Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. Am J Pathol. 2001;159(3):1069–77.
48. Zhu J et al. Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int. 2008;73(5):556–66.
49. Li H et al. SRC-family kinase Fyn phosphorylates the cytoplasmic domain of nephrin and modulates its interaction with podocin. J Am Soc Nephrol. 2004;15(12):3006–15.
50. Verma R et al. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006;116(5):1346–59.
51. Tryggvason K, Pikkarainen T, Patrakka J. Nck links nephrin to actin in kidney podocytes. Cell. 2006;125(2):221–4.
52. Jones N et al. Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature. 2006;440(7085):818–23.
53. Na J et al. Diet-induced podocyte dysfunction in drosophila and mammals. Cell Rep. 2015;12(4):636–47.
54. Doublier S et al. Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes. 2003;52(4):1023–30.
55. Coward RJ et al. Nephrin is critical for the action of insulin on human glomerular podocytes. Diabetes. 2007;56(4):1127–35.
56. Welsh GI et al. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 2010;12(4):329–40.
57. Veron D et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int. 2010;77(11):989–99.
58. Huber TB et al. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol. 2003;23(14):4917–28.
59. Blattner SM et al. Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 2013;84(5):920–30.
60. Yu H et al. Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol Cell Biol. 2013;33(23):4755–64.
61. Lin, J.S., et al., Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy. J Pathol 2015.
62. Akilesh S et al. Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest. 2011;121(10):4127–37.
63. Gee HY et al. ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J Clin Invest. 2013;123(8):3243–53.
64. Danesh FR et al. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy. Proc Natl Acad Sci U S A. 2002;99(12):8301–5.
65. Peng F et al. RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes. 2008;57(6):1683–92.
66. Vogelmann SU et al. Urinary excretion of viable podocytes in health and renal disease. Am J Physiol Renal Physiol. 2003;285(1):F40–8.
67. Mathew S et al. Integrins in renal development. Pediatr Nephrol. 2012;27(6):891–900.
68. Chen HC et al. Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci. 2000;67(19):2345–53.
69. Regoli M, Bendayan M. Alterations in the expression of the alpha 3 beta 1 integrin in certain membrane domains of the glomerular epithelial cells (podocytes) in diabetes mellitus. Diabetologia. 1997;40(1):15–22.
70. Susztak K et al. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006;55(1):225–33.
71. Eid AA et al. Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes. 2009;58(5):1201–11.
72. Eid AA et al. Mammalian target of rapamycin regulates Nox4-mediated podocyte depletion in diabetic renal injury. Diabetes. 2013;62(8):2935–47. This study showed that mTOR drives production of Nox-4 derived ROS generation and podocyte death. Inhibiting mTOR or NADPH oxidase was shown to be beneficial in animal models.
73. Schiffer M et al. Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001;108(6):807–16.
74. Li JH et al. Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. Faseb j. 2004;18(1):176–8.
75. Li Y et al. Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. Am J Pathol. 2008;172(2):299–308.
76. Abe Y et al. TGF-beta1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. Am J Physiol Renal Physiol. 2013;305(10):F1477–90.
77. Das R et al. Upregulation of mitochondrial Nox4 mediates TGF-beta-induced apoptosis in cultured mouse podocytes. Am J Physiol Renal Physiol. 2014;306(2):F155–67.
78. Hartleben B et al. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010;120(4):1084–96.
79. Lenoir O et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy. 2015;11(7):1130–45.
80. Shahzad K et al. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 2015;87(1):74–84. This study showed that Nlrp3-inflammasome activation aggravates diabetic nephropathy. Blocking ROS and Nlrp3-inflammasome might be protective in diabetic kidney disease.
81. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–5.
82. Godel M et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197–209.
83. Inoki K et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181–96.
84. Niranjan T et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med. 2008;14(3):290–8.
85. Lin CL et al. Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy. Diabetes. 2010;59(8):1915–25.
86. Sweetwyne MT, et al. Notch1 and Notch2 in podocytes play differential roles during diabetic nephropathy development. Diabetes, 2015; 64(12):4099–111. This study looked at different Notch receptors in vivo and demonstrated that Notch1 and Notch2 have divergent roles in diabetic nephropathy.
87. Kato H et al. Wnt/beta-catenin pathway in podocytes integrates cell adhesion, differentiation, and survival. J Biol Chem. 2011;286(29):26003–15.
88. Ichikawa I et al. Podocyte damage damages podocytes: autonomous vicious cycle that drives local spread of glomerular sclerosis. Curr Opin Nephrol Hypertens. 2005;14(3):205–10.
89. Sharma K et al. Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest. 2008;118(5):1645–56.
90. Hemmelgarn BR et al. Relation between kidney function, proteinuria, and adverse outcomes. Jama. 2010;303(5):423–9.
91. Malaga-Dieguez L, Susztak K. ADCK4 “reenergizes” nephrotic syndrome. J Clin Invest. 2013;123(12):4996–9.
92. Hackl MJ et al. Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in new mouse models with fluorescent lineage tags. Nat Med. 2013;19(12):1661–6.
93. Eng DG et al. Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis. Kidney Int. 2015;88(5):999–1012.
94. Berger K et al. The regenerative potential of parietal epithelial cells in adult mice. J Am Soc Nephrol. 2014;25(4):693–705.
95. Ronconi E et al. Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol. 2009;20(2):322–32.
96. Guhr SS et al. The expression of podocyte-specific proteins in parietal epithelial cells is regulated by protein degradation. Kidney Int. 2013;84(3):532–44.
97. Appel D et al. Recruitment of podocytes from glomerular parietal epithelial cells. J Am Soc Nephrol. 2009;20(2):333–43.