Acta Diabetologica

, Volume 55, Issue 11, pp 1105–1111 | Cite as

Glomerular endothelial cells versus podocytes as the cellular target in diabetic nephropathy

  • Silvia Maestroni
  • Gianpaolo ZerbiniEmail author
Review Article
Part of the following topical collections:
  1. Diabetic Nephropathy


It usually takes several years (in some cases, decades) for predisposed individuals to move from the onset of type 1 or type 2 diabetes to the development of microalbuminuria, the first sign of diabetic nephropathy. This long, complication-free, period represents the best possible moment to start a successful preventive strategy (primary prevention) aimed to avoid or at least to postpone the increase of albumin excretion rate. Prevention is based on understanding and counteracting the initial mechanisms leading to the development of the disease and unfortunately, in case of diabetic nephropathy, most of them remain unclear. Little is also known about which, among endothelial cells and podocytes, represent the first glomerular target of the complication. Selective damage of the endothelium or of the podocyte results, as a common consequence, in an increase of albumin excretion rate. Albuminuria by itself cannot therefore be of help to solve the case. Endothelium and podocytes are involved in a continuous cross-talk and by studying the impact of diabetes on this “communication” process it should be possible to obtain some information regarding the weak component of the glomerular filter. Finally, the careful investigation of the mechanisms leading to the development podocyturia, a recently identified glomerular dysfunction associated to the pathogenesis of diabetic nephropathy, could contribute to shed some more light on the very early stages of this complication.


Glomerular endothelial cells Podocytes Diabetic nephropathy Prevention Podocyturia 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not required because no studies in humans were performed.


  1. 1.
    Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D et al (2014) Changes in diabetes-related complications in the United States, 1990–2010. N Engl J Med 370(16):1514–1523. CrossRefPubMedGoogle Scholar
  2. 2.
    Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR (1985) The changing natural history of nephropathy in type I diabetes. Am J Med 78(5):785–794CrossRefGoogle Scholar
  3. 3.
    Keen H, Chlouverakis C (1964) Urinary albumin excretion and diabetes mellitus. Lancet 2(7370):1155–1156CrossRefGoogle Scholar
  4. 4.
    Parvanova AI, Trevisan R, Iliev IP, Dimitrov BD, Vedovato M, Tiengo A et al (2006) Insulin resistance and microalbuminuria: a cross-sectional, case-control study of 158 patients with type 2 diabetes and different degrees of urinary albumin excretion. Diabetes 55(5):1456–1462. CrossRefPubMedGoogle Scholar
  5. 5.
    De Cosmo S, Motterlini N, Prudente S, Pellegrini F, Trevisan R, Bossi A et al (2009) Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: evidence from BENEDICT. Diabetes 58(12):2920–2929. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Haraldsson B, Nystrom J, Deen WM (2008) Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev 88(2):451–487. CrossRefPubMedGoogle Scholar
  7. 7.
    Satchell SC, Braet F (2009) Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol 296(5):F947–F956. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rostgaard J, Qvortrup K (1997) Electron microscopic demonstrations of filamentous molecular sieve plugs in capillary fenestrae. Microvasc Res 53(1):1–13CrossRefGoogle Scholar
  9. 9.
    Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG (2007) The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch 454(3):345–359. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Miner JH (2012) The glomerular basement membrane. Exp Cell Res 318(9):973–978. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Timpl R (1989) Structure and biological activity of basement membrane proteins. Eur J Biochem 180(3):487–502CrossRefGoogle Scholar
  12. 12.
    Grahammer F (2017) New structural insights into podocyte biology. Cell Tissue Res 369(1):5–10. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Grahammer F, Schell C, Huber TB (2013) The podocyte slit diaphragm–from a thin grey line to a complex signalling hub. Nat Rev Nephrol 9(10):587–598. CrossRefPubMedGoogle Scholar
  14. 14.
    Lawrence MG, Altenburg MK, Sanford R, Willett JD, Bleasdale B, Ballou B et al (2017) Permeation of macromolecules into the renal glomerular basement membrane and capture by the tubules. Proc Natl Acad Sci USA 114(11):2958–2963. CrossRefPubMedGoogle Scholar
  15. 15.
    Obeidat M, Obeidat M, Ballermann BJ (2012) Glomerular endothelium: a porous sieve and formidable barrier. Exp Cell Res 318(9):964–972. CrossRefPubMedGoogle Scholar
  16. 16.
    Ryan GB, Karnovsky MJ (1976) Distribution of endogenous albumin in the rat glomerulus: Role of hemodynamic factors in glomerular barrier function. Kidney Int 9(1):36–45CrossRefGoogle Scholar
  17. 17.
    Holthofer H, Ahola H, Solin ML, Wang S, Palmen T, Luimula P et al (1999) Nephrin localizes at the podocyte filtration slit area and is characteristically spliced in the human kidney. Am J Pathol 155(5):1681–1687. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Tryggvason K (1999) Unraveling the mechanisms of glomerular ultrafiltration: nephrin, a key component of the slit diaphragm. J Am Soc Nephrol 10(11):2440–2445PubMedGoogle Scholar
  19. 19.
    Schlöndorff D, Wyatt CM, Campbell KN (2017) Revisiting the determinants of the glomerular filtration barrier: what goes round must come round. Kidney Int 92(3):533–536. CrossRefPubMedGoogle Scholar
  20. 20.
    Zerbini G, Bonfanti R, Meschi F, Bognetti E, Paesano PL, Gianolli L et al (2006) Persistent renal hypertrophy and faster decline of glomerular filtration rate precede the development of microalbuminuria in type 1 diabetes. Diabetes 55(9):2620–2625. CrossRefPubMedGoogle Scholar
  21. 21.
    Lorenzi M, Cagliero E, Toledo S (1985) Glucose toxicity for human endothelial cells in culture. Delayed replication, disturbed cell cycle, and accelerated death. Diabetes 34(7):621–627CrossRefGoogle Scholar
  22. 22.
    Nieuwdorp M, Mooij HL, Kroon J, Atasever B, Spaan JA, Ince C et al (2006) Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes 55(4):1127–1132CrossRefGoogle Scholar
  23. 23.
    Deckert T, Kofoed-Enevoldsen A, Vidal P, Nørgaard K, Andreasen HB, Feldt-Rasmussen B (1993) Size- and charge selectivity of glomerular filtration in type 1 (insulin-dependent) diabetic patients with and without albuminuria. Diabetologia 36(3):244–251CrossRefGoogle Scholar
  24. 24.
    Satchell S (2013) The role of the glomerular endothelium in albumin handling. Nat Rev Nephrol 9(12):717–725. CrossRefPubMedGoogle Scholar
  25. 25.
    Morigi M, Buelli S, Angioletti S, Zanchi C, Longaretti L, Zoja C et al (2005) In response to protein load podocytes reorganize cytoskeleton and modulate endothelin–1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol 166(5):1309–1320. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Qi H, Casalena G, Shi S, Yu L, Ebefors K, Sun Y et al (2017) Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility. Diabetes 66(3):763–778. CrossRefPubMedGoogle Scholar
  27. 27.
    Caramori ML, Parks A, Mauer M (2013) Renal lesions predict progression of diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol 24(7):1175–1181. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Walker F (1973) The origin, turnover and removal of glomerular basement-membrane. J Pathol 110(3):233–244. CrossRefPubMedGoogle Scholar
  29. 29.
    Marshall CB (2016) Rethinking glomerular basement membrane thickening in diabetic nephropathy: adaptive or pathogenic? Am J Physiol Renal Physiol 311:F831–F843. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Anil Kumar P, Welsh GI, Saleem MA, Menon RK (2014) Molecular and cellular events mediating glomerular podocyte dysfunction and depletion in diabetes mellitus. Front Endocrinol (Lausanne) 5:151. CrossRefGoogle Scholar
  31. 31.
    Sagoo MK, Gnudi L (2018) Diabetic nephropathy: Is there a role for oxidative stress? Free Radic Biol Med 116:50–63. CrossRefPubMedGoogle Scholar
  32. 32.
    Diez-Sampedro A, Lenz O, Fornoni A (2011) Podocytopathy in diabetes: a metabolic and endocrine disorder. Am J Kidney Dis 58(4):637–646. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yamaguchi Y, Iwano M, Suzuki D, Nakatani K, Kimura K, Harada K et al (2009) Epithelial–mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am J Kidney Dis 54(4):653–664. CrossRefPubMedGoogle Scholar
  34. 34.
    Salmon AH, Toma I, Sipos A, Muston PR, Harper SJ, Bates DO et al(2007) Evidence for restriction of fluid and solute movement across the glomerular capillary wall by the subpodocytes pace. Am J Physiol Renal Physiol 293(6):F1777–F1786. CrossRefPubMedGoogle Scholar
  35. 35.
    Coward RJ, Welsh GI, Yang J, Tasman C, Lennon R, Koziell A et al (2005) The human glomerular podocyte is a novel target for insulin action. Diabetes 54(11):3095–3102CrossRefGoogle Scholar
  36. 36.
    Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R et al (2010) Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metab 12(4):329–340. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fu J, Lee K, Chuang PY, Liu Z, He JC (2015) Glomerular endothelial cell injury and cross talk in diabetic kidney disease. Am J Physiol Renal Physiol 308(4):F287–F297. CrossRefPubMedGoogle Scholar
  38. 38.
    Cooper ME, Vranes D, Youssef S, Stacker SA, Cox AJ, Rizkalla B et al (1999) Increased renal expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 in experimental diabetes. Diabetes 48(11):2229–2239CrossRefGoogle Scholar
  39. 39.
    Flyvbjerg A, Dagnaes-Hansen F, De Vriese AS, Schrijvers BF, Tilton RG, Rasch R (2002) Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes 51(10):3090–3094CrossRefGoogle Scholar
  40. 40.
    Sison K, Eremina V, Baelde H, Min W, Hirashima M, Fantus IG et al (2010) Glomerular structure and function require paracrine, not autocrine, VEGF-VEGFR-2 signaling. J Am Soc Nephrol 21(10):1691–1701. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Guan F, Villegas G, Teichman J, Mundel P, Tufro A (2006) Autocrine VEGF-A system in podocytes regulates podocin and its interaction with CD2AP. Am J Physiol Renal Physiol 291(2):F422–F428. CrossRefPubMedGoogle Scholar
  42. 42.
    Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J et al (2007) Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med 13(11):1349–1358. CrossRefPubMedGoogle Scholar
  43. 43.
    Wu X, Gao Y, Xu L, Dang W, Yan H, Zou D et al (2017) Exosomes from high glucose-treated glomerular endothelial cells trigger the epithelial–mesenchymal transition and dysfunction of podocytes. Sci Rep 7(1):9371. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Satchell SC, Harper SJ, Tooke JE, Kerjaschki D, Saleem MA, Mathieson PW (2002) Human podocytes express angiopoietin 1, a potential regulator of glomerular vascular endothelial growth factor. J Am Soc Nephrol 13(2):544–550PubMedGoogle Scholar
  45. 45.
    Thurston G, Rudge JS, Ioffe E, Zhou H, Ross L, Croll SD et al (2000) Angiopoietin-1 protects the adult vasculature against plasma leakage. Nat Med 6(4):460–463. CrossRefPubMedGoogle Scholar
  46. 46.
    Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C et al (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277(5322):55–60CrossRefGoogle Scholar
  47. 47.
    Dessapt-Baradez C, Woolf AS, White KE, Pan J, Huang JL, Hayward AA et al (2014) Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease. J Am Soc Nephrol 25(1):33–42. CrossRefPubMedGoogle Scholar
  48. 48.
    Lim HS, Lip GY, Blann AD (2005) Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. Atherosclerosis 180(1):113–118. CrossRefPubMedGoogle Scholar
  49. 49.
    Sayyed SG1, Hägele H, Kulkarni OP, Endlich K, Segerer S, Eulberg D et al (2009) Podocytes produce homeostatic chemokine stromal cell-derived factor-1/CXCL12, which contributes to glomerulosclerosis, podocyte loss and albuminuria in a mouse model of type 2 diabetes. Diabetologia 52(11):2445–2454. CrossRefPubMedGoogle Scholar
  50. 50.
    Tufro A (2017) Podocyte shape regulation by semaphorin 3A and MICAL-1. Methods Mol Biol 1493:393–399. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Yuen DA, Stead BE, Zhang Y, White KE, Kabir MG, Thai K et al (2012) eNOS deficiency predisposes podocytes to injury in diabetes. J Am Soc Nephrol 23(11):1810–1823. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Zanchi A, Moczulski DK, Hanna LS, Wantman M, Warram JH, Krolewski AS (2000) Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int 57(2):405–413. CrossRefPubMedGoogle Scholar
  53. 53.
    Bock F, Shahzad K, Wang H, Stoyanov S, Wolter J, Dong W et al (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci USA 110(2):648–653. CrossRefPubMedGoogle Scholar
  54. 54.
    Zhang M-Z, Wang Y, Paueksakon P, Harris RC (2014) Epidermal growth factor receptor inhibition slows progression of diabetic nephropathy in association with a decrease in endoplasmic reticulum stress and an increase in autophagy. Diabetes 63(6):2063–2072. CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Yin GN, Jin HR, Choi MJ, Limanjaya A, Ghatak K, Minh NN et al (2018) Pericyte-derived Dickkopf2 regenerates damaged penile neurovasculature through an angiopoietin-1-Tie2 pathway. Diabetes 67(6):1149–1161. CrossRefPubMedGoogle Scholar
  56. 56.
    Burghardt T, Hochapfel F, Salecker B, Meese C, Gröne HJ, Rachel R et al (2015) Advanced electron microscopic techniques provide a deeper insight into the peculiar features of podocytes. Am J Physiol Renal Physiol 309(12):F1082–F1089. CrossRefPubMedGoogle Scholar
  57. 57.
    Musah S, Mammoto A, Ferrante TC, Jeanty SSF, Hirano-Kobayashi M, Mammoto T et al (2017) Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat Biomed. CrossRefGoogle Scholar
  58. 58.
    Steffes MW, Osterby R, Chavers B, Mauer SM (1989) Mesangial expansion as a central mechanism for loss of kidney function in diabetic patients. Diabetes 38(9):1077–1081CrossRefGoogle Scholar
  59. 59.
    Lazzeri E, Romagnani P (2015) Podocyte biology: differentiation of parietal epithelial cells into podocytes. Nat Rev Nephrol 11(1):7–8. CrossRefPubMedGoogle Scholar
  60. 60.
    Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG et al (1997) Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99(2):342–348. CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ziyadeh FN, Wolf G (2008) Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. Curr Diabetes Rev 4(1):39–45CrossRefGoogle Scholar
  62. 62.
    Yasuda-Yamahara M, Kume S, Tagawa A, Maegawa H, Uzu T (2015) Emerging role of podocyte autophagy in the progression of diabetic nephropathy. Autophagy 11(12):2385–2386. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Kriz W, Shirato I, Nagata M, LeHir M, Lemley KV (2013) The podocyte’s response to stress: the enigma of foot process effacement. Am J Physiol Renal Physiol 304(4):F333–F347. CrossRefPubMedGoogle Scholar
  64. 64.
    Vogelmann SU, Nelson WJ, Myers BD, Lemley KV (2003) Urinary excretion of viable podocytes in health and renal disease. Am J Physiol Renal Physiol 285(1):F40–F48. CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Maestroni S, Maestroni A, Dell’Antonio G, Gabellini D, Terzi S, Spinello A et al (2014) Viable podocyturia in healthy individuals: implications for podocytopathies. Am J Kidney Dis 64(6):1003–1005. CrossRefPubMedGoogle Scholar
  66. 66.
    Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Ebihara I et al (2000) Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant 15(9):1379–1383CrossRefGoogle Scholar
  67. 67.
    Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M (2007) Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes 56(8):2155–2160. CrossRefPubMedGoogle Scholar
  68. 68.
    Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K et al (2012) Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int 82(9):1010–1017. CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Conti S, Perico N, Novelli R, Carrara C, Benigni A, Remuzzi G (2018) Early and late scanning electron microscopy findings in diabetic kidney disease. Sci Rep 8(1):4909. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Complications of Diabetes Unit, Division of Immunology, Transplantation and Infectious Diseases, Diabetes Research Institute (DRI)IRCCS San Raffaele Scientific InstituteMilanoItaly

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