The Role of Podocytes and Podocyte-Associated Biomarkers in Diagnosis and Treatment of Diabetic Kidney Disease

Igor Kravets, Sandeep K Mallipattu, Igor Kravets, Sandeep K Mallipattu

Abstract

Diabetic kidney disease (DKD) is an important public health problem. Podocyte injury is a central event in the mechanism of DKD development. Podocytes are terminally differentiated, highly specialized glomerular visceral epithelial cells critical for the maintenance of the glomerular filtration barrier. Although potential mechanisms by which diabetic milieu contributes to irreversible loss of podocytes have been described, identification of markers that prognosticate either the development of DKD or the progression to end-stage kidney disease (ESKD) have only recently made it to the forefront. Currently, the most common marker of early DKD is microalbuminuria; however, this marker has significant limitations: not all diabetic patients with microalbuminuria will progress to ESKD and as many as 30% of patients with DKD have normal urine albumin levels. Several novel biomarkers indicating glomerular or tubular damage precede microalbuminuria, suggesting that the latter develops when significant kidney injury has already occurred. Because podocyte injury plays a key role in DKD pathogenesis, identification of markers of early podocyte injury or loss may play an important role in the early diagnosis of DKD. Such biomarkers in the urine include podocyte-released microparticles as well as expression of podocyte-specific markers. Here, we review the mechanisms by which podocyte injury contributes to DKD as well as key markers that have been recently implicated in the development and/or progression of DKD and might serve to identify individuals that require earlier preventative care and treatment in order to slow the progression to ESKD.

Keywords: biological markers; biomarkers; diabetes; diabetic kidney disease; podocytes.

© Endocrine Society 2020.

References

    1. Saran R, Robinson B, Abbott KC, et al. . US renal data system 2016 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2017;69(3 Suppl 1):A7–A8.
    1. Centers for Disease Control and Prevention. 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):1361–1366.
    1. Drummond K, Mauer M; International Diabetic Nephropathy Study Group The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. Diabetes. 2002;51(5):1580–1587.
    1. Ponchiardi C, Mauer M, Najafian B. Temporal profile of diabetic nephropathy pathologic changes. Curr Diab Rep. 2013;13(4):592–599.
    1. Dahlquist G, Stattin EL, Rudberg S. Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients. Nephrol Dial Transplant. 2001;16(7):1382–1386.
    1. Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med. 2002;346(15):1145–1151.
    1. Kramer HJ, Nguyen QD, Curhan G, Hsu CY. Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. Jama. 2003;289(24):3273–3277.
    1. Tziomalos K, Athyros VG. Diabetic nephropathy: new risk factors and improvements in diagnosis. Rev Diabet Stud. 2015;12(1-2):110–118.
    1. Tan AL, Forbes JM, Cooper ME. AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol. 2007;27(2):130–143.
    1. Leehey DJ, Singh AK, Alavi N, Singh R. Role of angiotensin II in diabetic nephropathy. Kidney Int Suppl. 2000;77:S93–S98.
    1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456–1462.
    1. Lewis EJ, Hunsicker LG, Clarke WR, et al. ; Collaborative Study Group Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–860.
    1. Veron D, Bertuccio CA, Marlier A, et al. . Podocyte vascular endothelial growth factor (Vegf164) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia. 2011;54(5):1227–1241.
    1. Sugimoto H, Hamano Y, Charytan D, 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):12605–12608.
    1. Iglesias-de la Cruz MC, Ziyadeh FN, Isono M, 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):901–913.
    1. Fujimoto M, Maezawa Y, Yokote K, et al. . Mice lacking Smad3 are protected against streptozotocin-induced diabetic glomerulopathy. Biochem Biophys Res Commun. 2003;305(4):1002–1007.
    1. Hathaway CK, Gasim AM, Grant R, et al. . Low TGFbeta1 expression prevents and high expression exacerbates diabetic nephropathy in mice. Proc Natl Acad Sci U S A. 2015;112(18):5815–5820.
    1. Shen Z, Fang Y, Xing T, Wang F. Diabetic nephropathy: from pathophysiology to treatment. J Diabetes Res. 2017;2017:2379432.
    1. Reiser J, Altinias MM. Podocytes. F1000Res. 2016;5:F1000 Faculty Rev-114.
    1. Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88(2):451–487.
    1. Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83(1):253–307.
    1. Weil EJ, Lemley KV, Mason CC, et al. . Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int. 2012;82(9):1010–1017.
    1. Wiggins JE, Goyal M, Sanden SK, 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):2953–2966.
    1. Wharram BL, Goyal M, Wiggins JE, 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):2941–2952.
    1. Mundel P, Shankland SJ. Podocyte biology and response to injury. J Am Soc Nephrol. 2002;13(12):3005–3015.
    1. Li X, Chuang PY, D’Agati VD, et al. . Nephrin preserves podocyte viability and glomerular structure and function in adult kidneys. J Am Soc Nephrol. 2015;26(10):2361–2377.
    1. Zhu J, Sun N, Aoudjit L, et al. . Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int. 2008;73(5):556–566.
    1. Verma R, Kovari I, Soofi A, Nihalani D, Patrie K, Holzman LB. Nephrin ectodomain engagement results in Src kinase activation, nephrin phosphorylation, Nck recruitment, and actin polymerization. J Clin Invest. 2006;116(5):1346–1359.
    1. Simons M, Schwarz K, Kriz W, et al. . Involvement of lipid rafts in nephrin phosphorylation and organization of the glomerular slit diaphragm. Am J Pathol. 2001;159(3):1069–1077.
    1. Jones N, Blasutig IM, Eremina V, et al. . Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature. 2006;440(7085):818–823.
    1. Tryggvason K, Pikkarainen T, Patrakka J. Nck links nephrin to actin in kidney podocytes. Cell. 2006;125(2):221–224.
    1. Doublier S, Salvidio G, Lupia E, 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):1023–1030.
    1. Welsh GI, Hale LJ, Eremina V, et al. . Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab. 2010;12(4):329–340.
    1. Coward RJ, Welsh GI, Koziell A, et al. . Nephrin is critical for the action of insulin on human glomerular podocytes. Diabetes. 2007;56(4):1127–1135.
    1. Peng F, Wu D, Gao B, et al. . RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes. 2008;57(6):1683–1692.
    1. Blattner SM, Hodgin JB, Nishio M, et al. . Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 2013;84(5):920–930.
    1. Danesh FR, Sadeghi MM, Amro N, 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):8301–8305.
    1. Yu H, Suleiman H, Kim AH, et al. . Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol Cell Biol. 2013;33(23):4755–4764.
    1. Chen HC, Chen CA, Guh JY, Chang JM, Shin SJ, Lai YH. Altering expression of alpha3beta1 integrin on podocytes of human and rats with diabetes. Life Sci. 2000;67(19):2345–2353.
    1. Mathew S, Chen X, Pozzi A, Zent R. Integrins in renal development. Pediatr Nephrol. 2012;27(6):891–900.
    1. Lin JS, Susztak K. Podocytes: the weakest link in diabetic kidney disease? Curr Diab Rep. 2016;16(5):45.
    1. Susztak K, Raff AC, Schiffer M, Böttinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes. 2006;55(1):225–233.
    1. Eid AA, Gorin Y, Fagg BM, et al. . Mechanisms of podocyte injury in diabetes: role of cytochrome P450 and NADPH oxidases. Diabetes. 2009;58(5):1201–1211.
    1. Noma K, Rikitake Y, Oyama N, et al. . ROCK1 mediates leukocyte recruitment and neointima formation following vascular injury. J Clin Invest. 2008;118(5):1632–1644.
    1. Riento K, Ridley AJ. Rocks: multifunctional kinases in cell behaviour. Nat Rev Mol Cell Biol. 2003;4(6):446–456.
    1. Horne SJ, Vasquez JM, Guo Y, et al. . Podocyte-specific loss of Krüppel-like factor 6 increases mitochondrial injury in diabetic kidney disease. Diabetes. 2018;67(11):2420–2433.
    1. Schiffer M, Bitzer M, Roberts IS, et al. . Apoptosis in podocytes induced by TGF-beta and Smad7. J Clin Invest. 2001;108(6):807–816.
    1. Li JH, Huang XR, Zhu HJ, 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):176–178.
    1. Lenoir O, Jasiek M, Hénique C, et al. . Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy. 2015;11(7):1130–1145.
    1. Hartleben B, Gödel M, Meyer-Schwesinger C, et al. . Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest. 2010;120(4):1084–1096.
    1. Shahzad K, Bock F, Dong W, et al. . Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 2015;87(1):74–84.
    1. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10(3):210–215.
    1. Kim NH. Podocyte hypertrophy in diabetic nephropathy. Nephrology (Carlton). 2005;10(Suppl):S14–S16.
    1. Inoki K, Mori H, Wang J, et al. . mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest. 2011;121(6):2181–2196.
    1. Gödel M, Hartleben B, Herbach N, et al. . Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest. 2011;121(6):2197–2209.
    1. Sweetwyne MT, Gruenwald A, Niranjan T, Nishinakamura R, Strobl LJ, Susztak K. Notch1 and Notch2 in podocytes play differential roles during diabetic nephropathy development. Diabetes. 2015;64(12):4099–4111.
    1. Niranjan T, Bielesz B, Gruenwald A, et al. . The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat Med. 2008;14(3):290–298.
    1. Lin CL, Wang FS, Hsu YC, et al. . Modulation of notch-1 signaling alleviates vascular endothelial growth factor-mediated diabetic nephropathy. Diabetes. 2010;59(8):1915–1925.
    1. Kato H, Gruenwald A, Suh JH, et al. . Wnt/β-catenin pathway in podocytes integrates cell adhesion, differentiation, and survival. J Biol Chem. 2011;286(29):26003–26015.
    1. Fu J, Akat KM, Sun Z, et al. . Single-Cell RNA profiling of glomerular cells shows dynamic changes in experimental diabetic kidney disease. J Am Soc Nephrol. 2019;30(4):533–545.
    1. Ichikawa I, Ma J, Motojima M, Matsusaka T. Podocyte damage damages podocytes: autonomous vicious cycle that drives local spread of glomerular sclerosis. Curr Opin Nephrol Hypertens. 2005;14(3):205–210.
    1. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS GROUP Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225–232.
    1. An JH, Cho YM, Yu HG, et al. . The clinical characteristics of normoalbuminuric renal insufficiency in Korean type 2 diabetic patients: a possible early stage renal complication. J Korean Med Sci. 2009;24(Suppl):S75–S81.
    1. Matheson A, Willcox MD, Flanagan J, Walsh BJ. Urinary biomarkers involved in type 2 diabetes: a review. Diabetes Metab Res Rev. 2010;26(3):150–171.
    1. Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P. Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes. 2003;52(4):1031–1035.
    1. Wang C, Li C, Gong W, Lou T. New urinary biomarkers for diabetic kidney disease. Biomark Res. 2013;1(1):9–12.
    1. Nakamura T, Ushiyama C, Suzuki S, et al. . Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant. 2000;15(9):1379–1383.
    1. Jim B, Ghanta M, Qipo A, et al. . Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study. Plos One. 2012;7(5):e36041.
    1. Kandasamy Y, Smith R, Lumbers ER, Rudd D. Nephrin - a biomarker of early glomerular injury. Biomark Res. 2014;2:21.
    1. Alter ML, Kretschmer A, Von Websky K, et al. . Early urinary and plasma biomarkers for experimental diabetic nephropathy. Clin Lab. 2012;58(7-8):659–671.
    1. Chang JH, Paik SY, Mao L, et al. . Diabetic kidney disease in FVB/NJ Akita mice: temporal pattern of kidney injury and urinary nephrin excretion. Plos One. 2012;7(4):e33942.
    1. Ng DP, Tai BC, Tan E, et al. . Nephrinuria associates with multiple renal traits in type 2 diabetes. Nephrol Dial Transplant. 2011;26(8):2508–2514.
    1. do Nascimento JF, Canani LH, Gerchman F, et al. . Messenger RNA levels of podocyte-associated proteins in subjects with different degrees of glucose tolerance with or without nephropathy. BMC Nephrol. 2013;14:214.
    1. Wada Y, Abe M, Moritani H, et al. . Original Research: Potential of urinary nephrin as a biomarker reflecting podocyte dysfunction in various kidney disease models. Exp Biol Med (Maywood). 2016;241(16):1865–1876.
    1. Habara P, Marecková H, Sopková Z, et al. . A novel method for the estimation of podocyte injury: podocalyxin-positive elements in urine. Folia Biol (Praha). 2008;54(5):162–167.
    1. Hara M, Yamagata K, Tomino Y, et al. . Urinary podocalyxin is an early marker for podocyte injury in patients with diabetes: establishment of a highly sensitive ELISA to detect urinary podocalyxin. Diabetologia. 2012;55(11):2913–2919.
    1. Viedt C, Dechend R, Fei J, Hänsch GM, Kreuzer J, Orth SR. MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-kappaB and activating protein-1. J Am Soc Nephrol. 2002;13(6):1534–1547.
    1. Wada T, Furuichi K, Sakai N, et al. . Up-regulation of monocyte chemoattractant protein-1 in tubulointerstitial lesions of human diabetic nephropathy. Kidney Int. 2000;58(4):1492–1499.
    1. Tesch GH. MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy. Am J Physiol Renal Physiol. 2008;294(4):F697–F701.
    1. Fufaa GD, Weil EJ, Nelson RG, et al. ; CKD Biomarkers Consortium and the RASS Investigators Urinary monocyte chemoattractant protein-1 and hepcidin and early diabetic nephropathy lesions in type 1 diabetes mellitus. Nephrol Dial Transplant. 2015;30(4):599–606.
    1. Morii T, Fujita H, Narita T, et al. . Association of monocyte chemoattractant protein-1 with renal tubular damage in diabetic nephropathy. J Diabetes Complications. 2003;17(1):11–15.
    1. Zheng M, Lv LL, Ni J, et al. . Urinary podocyte-associated mRNA profile in various stages of diabetic nephropathy. Plos One. 2011;6(5):e20431.
    1. Yanagida-Asanuma E, Asanuma K, Kim K, et al. . Synaptopodin protects against proteinuria by disrupting Cdc42:IRSp53:Mena signaling complexes in kidney podocytes. Am J Pathol. 2007;171(2):415–427.
    1. Ha TS, Hong EJ, Han GD. Diabetic conditions downregulate the expression of CD2AP in podocytes via PI3-K/Akt signalling. Diabetes Metab Res Rev. 2015;31(1):50–60.
    1. Dandapani SV, Sugimoto H, Matthews BD, et al. . Alpha-actinin-4 is required for normal podocyte adhesion. J Biol Chem. 2007;282(1):467–477.
    1. Shono A, Tsukaguchi H, Yaoita E, et al. . Podocin participates in the assembly of tight junctions between foot processes in nephrotic podocytes. J Am Soc Nephrol. 2007;18(9):2525–2533.
    1. Niewczas MA, Gohda T, Skupien J, et al. . Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol. 2012;23(3):507–515.
    1. Niewczas MA, Pavkov ME, Skupien J, et al. . A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nat Med. 2019;25(5):805–813.
    1. Burger D, Schock S, Thompson CS, Montezano AC, Hakim AM, Touyz RM. Microparticles: biomarkers and beyond. Clin Sci (Lond). 2013;124(7):423–441.

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