Pathogenesis of Diabetic Glomerulopathy: The Role of Glomerular Hemodynamic Factors

  • Sharon Anderson


Glomerular hyperfiltration in insulin-dependent (Type 1) diabetes mellitus of short duration has been recognized for many years [1–3], with increments in renal plasma flow (RPF) and nephromegaly [3]. With the finding of early hyperfiltration, Stalder and Schmid proposed that these early functional changes may predispose the subsequent development of diabetic glomerulopathy [1]. Early support for the hypothesis that renal hyperperfusion and hyperfiltration contribute to diabetic glomerulopathy emanated from the finding of diabetic glomerulopathy only in the non-stenosed kidney in the setting of unilateral renal artery stenosis [4].


Diabetic Nephropathy Angiotensin Converting Enzyme Inhibitor Atrial Natriuretic Peptide Mesangial Cell Experimental Diabetes 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Stalder G, Schmid R. 1959. Severe functional disorders of glomerular capillaries and renal hemodynamics in treated diabetes mellitus during childhood. Ann Paediatr, 193:129–138.PubMedGoogle Scholar
  2. 2.
    Ditzel J, Junker K. 1972. Abnormal glomerular filtration rate, renal plasma flow and renal protein excretion in recent and short-term diabetes. Br Med J, 2:13–19.CrossRefPubMedGoogle Scholar
  3. 3.
    Mogensen CE, Andersen MJF. 1973. Increased kidney size and glomerular filtration rate in early juvenile diabetes. Diabetes, 22:706–712.PubMedGoogle Scholar
  4. 4.
    Berkman J, Rifkin H. 1973. Unilateral nodular diabetic glomerulosclerosis (Kimmelstiel-Wilson). Metabolism, 22:715–722.CrossRefPubMedGoogle Scholar
  5. 5.
    Vora J, Dolben J, Dean J, Williams JD, Owens DR, Peters JR. 1992. Renal hemodynamics in newly presenting non-insulin-dependent diabetics. Kidney fat, 41:829–835.CrossRefGoogle Scholar
  6. 6.
    Myers BD, Nelson RG, Williams GW, et al. 1991. Glomerular function in Pima Indians with non-insulin-dependent diabetes mellitus of recent origin. J Clin Invest, 88:524–530.CrossRefPubMedGoogle Scholar
  7. 7.
    Palmisano JJ, Lebovitz HE. 1989. Renal function in Black Americans with type II diabetes. J Diab Compl, 3:40–44.Google Scholar
  8. 8.
    Nelson RG, Bennett PH, Beck GJ, Tan M, Knowler WC, Mitch WE, Hirschman GH, Myers BD. 1996. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. New Engl J Med, 335:1636–1642.CrossRefPubMedGoogle Scholar
  9. 9.
    Nowack R, Raum E, Blum W, Ritz E. 1992. Renal hemodynamics in recent-onset Type II diabetes. Am J Kidney Dis, 20:342–347PubMedGoogle Scholar
  10. 10.
    Ritz E, Stefanski A. 1996. Diabetic nephropathy in Type II diabetes. Am J Kidney Dis, 27:167–194.CrossRefPubMedGoogle Scholar
  11. 11.
    Wirta O, Pasternack A, Laippala P, Turjanmaa V. 1996. Glomerular filtration rate and kidney size after six years disease duration in non-insulin-dependent diabetic subjects. Clin Nephrol, 45:10–71.PubMedGoogle Scholar
  12. 12.
    Mogensen CE. 1986. Early glomerular hyperfiltration in insulin-dependent diabetics and late nephropathy. Scand J Clin Lab Invest, 46:201–206.CrossRefPubMedGoogle Scholar
  13. 13.
    Rudberg S, Persson B,Dahlquist G. 1992. Increased glomerular filtration rate as a predictor of diabetic nephropathy — an 8 year prospective study. Kidney Int, 41. 822–828.CrossRefPubMedGoogle Scholar
  14. 14.
    Lervang H-H, Jensen S, Borchner-Mortensen J, Ditzel J. 1988. Early glomerular hyperfiltration and the development of late nephropathy in type 1 (insulin-dependent) diabetes mellitus. Diabetologia, 31:723–729.CrossRefPubMedGoogle Scholar
  15. 15.
    Yip JW, Jones SL, Wiseman M, Hill C,Viberti GC. 1996. Glomerular hyperfiltration in the prediction of nephropathy in IDDM. A 10-year followup study. Diabetes, 45: 1729–1733.CrossRefPubMedGoogle Scholar
  16. 16.
    Mogensen CE. 1994. Glomerular hyperfiltration in human diabetes. Diabetes Care, 17:770–775.PubMedGoogle Scholar
  17. 17.
    Vora JP, Peters JR, Williams JD. 1993. Evolution of renal hemodynamics in non-insulin-dependent diabetics (NIDDMs): a 2 year study. J Am Soc Nephrol, 4:310 (abstr).Google Scholar
  18. 18.
    Andersons. 1992. Antihypertensive therapy in experimental diabetes. J Am Soc Nephrol, 3 (Suppl 1):S86–S90.Google Scholar
  19. 19.
    O’Donnell MP, Kasiske BL, Keane WF. 1986. Glomerular hemodynamics and structural alterations in experimental diabetes. FASEB J, 2:2339–2347.Google Scholar
  20. 20.
    Park SK, Meyer TW. 1995. The effect of hyperglycemia on glomerular function in obese Zucker rats. J Lab Clin Med, 125:501–507.PubMedGoogle Scholar
  21. 21.
    Hostetter TH, Troy JL, Brenner BM. 1981. Glomerular hemodynamics in experimental diabetes mellitus. Kidney fat, 19:410–415.CrossRefGoogle Scholar
  22. 22.
    Zatz R, Meyer TW, Rennke HG, Brenner BM. 1985. Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci (US AX 82:5963–5967.CrossRefGoogle Scholar
  23. 23.
    Zatz R,Dunn BR, Meyer TW, Andersons, Rennke HG, Brenner BM. 1986. Prevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest, 77:1925–1930.CrossRefPubMedGoogle Scholar
  24. 24.
    Seyer-Hansen K. 1983. Renal hypertrophy fa experimental diabetes mellitus. Kidney Int, 23:643–646.CrossRefPubMedGoogle Scholar
  25. 25.
    Seyer-Hansen K, Hansen J, Gundersen HJG. 1980. Renal hypertrophy in experimental diabetes. A morphometric study. Diabetologia, 18:501–505.CrossRefPubMedGoogle Scholar
  26. 26.
    Steffes MW, Brown DM, Basgen JM, Mauer SM. 1980. Amelioration of mesangial volume and surface alterations following islet transplantation in diabetic rats. Diabetes, 29:509–515.PubMedGoogle Scholar
  27. 27.
    Mauer SM, Michael AF, Fish AJ, Brown DM. 1972. Spontaneous immunoglobulin and complement deposition in glomeruli of diabetic rats. Lab Invest, 27:488–494.PubMedGoogle Scholar
  28. 28.
    O’Donnell MP, Kasiske BL, Daniels FX, Keane WF. 1986. Effect of nephron loss on glomerular hemodynamics and morphology in diabetic rats. Diabetes, 35:1011–1015.CrossRefPubMedGoogle Scholar
  29. 29.
    Mauer SM, Steffes MW, Azar S, Sanbderg SK, Brown DM 1978. The effect of Goldblatt hypertension on development of the glomerular lesions of diabetes mellitus in the rat. Diabetes, 27:738–744.CrossRefPubMedGoogle Scholar
  30. 30.
    Hayashi K, Epstein M, Loutzenhiser R, Forster H. 1992. Impaired myogenic responsiveness of the afferent arteriole in streptozotocin-induced diabetic rats: role of eicosanoid derangements. J Am Soc Nephrol, 2:1578–1586.PubMedGoogle Scholar
  31. 31.
    Christensen PK, Hansen HP, Parving H-H. 1997. Impaired autoregulation of GFR in hypertensive non-insulin dependent diabetic patients. Kidney fat, 52:1369–1374.CrossRefGoogle Scholar
  32. 32.
    Christiansen JS, Gammelgaard J, Tronier B, Svendsen PA, Parving H-H. 1982. Kidney function and size in diabetics before and during initial insulin treatment. Kidney Int, 21:683–688.CrossRefPubMedGoogle Scholar
  33. 33.
    Parving H-H, Christiansen JS,Noer I, Tronier B, Mogensen CE. 1980. The effect of glucagon infusion on kidney function in short-term insulin-dependent juvenile diabetics. Diabetologia, 19:350–354.CrossRefPubMedGoogle Scholar
  34. 34.
    Christiansen JS, Gammelgaard J, Orskov H, Andersen AR, Telmer S, Parving H-H. 1980. Kidney function and size in normal subjects before and during growth hormone administration for one week. Eur J Clin Invest, 11:487–490.CrossRefGoogle Scholar
  35. 35.
    Vora J, Dolben J, Williams JD, Peters JR, Owens DR. 1993. Impact of initial treatment on renal function in newly-diagnosed Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia, 36:734–740.CrossRefPubMedGoogle Scholar
  36. 36.
    Stackhouse S, Miller PL, Park SK, Meyer TW. 1990. Reversals of glomerular hyperfiltration and renal hypertrophy by blood glucose normalization in diabetic rats. Diabetes, 39:989–995.CrossRefPubMedGoogle Scholar
  37. 37.
    Scholey JW, Meyer TW. 1989. Control of glomerular hypertension by insulin administration in diabetic rats. J Clin Invest, 83:1384–1389.CrossRefPubMedGoogle Scholar
  38. 38.
    Tucker BJ, Anderson CM, Thies RS, Collins RC, Blantz RC. 1992. Glomerular hemodynamic alterations during acute hyperinsulinemia in normal and diabetic rats. Kidney Int, 42:1160–1168.CrossRefPubMedGoogle Scholar
  39. 39.
    Sabbatini M, Sansone G, Uccello F, Giliberti A, Conte G, Andreucci VE. 1992. Early glycosylation products induce glomerular hyperfiltration in normal rats. Kidney Int, 42:875–881.CrossRefPubMedGoogle Scholar
  40. 40.
    Ortola FV, Ballermann BJ, Anderson S, Mendez RE, Brenner BM 1987. Elevated plasma atrial natriuretic peptide levels in diabetic rats. J Clin Invest, 80:670–674.CrossRefPubMedGoogle Scholar
  41. 41.
    Mattar AL, Fujihara CK, Ribeiro MO, DeNucci G, Zatz R. 1996. Renal effects of acute and chronic nitric oxide inhibition in experimental diabetes. Nephron, 74:136–143.CrossRefPubMedGoogle Scholar
  42. 42.
    Komers R, Allen TJ, Cooper ME. 1994. Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes. Diabetes, 43:1190–1197.CrossRefPubMedGoogle Scholar
  43. 43.
    Ballermann BJ, Skorecki KL, Brenner BM. 1984. Reduced glomerular angiotensin II receptor density in early untreated diabetes mellitus in the rat Am J Physiol, 247: F110–F116.Google Scholar
  44. 44.
    Wilkes BM, Kaplan R, Mento PF, Aynedjian H Macica CM, Schlondorff D, Bank N. 1992. Reduced glomerular thromboxane receptor sites and vasoconstrictor responses in diabetic rats. Kidney Int, 41:992–999.CrossRefPubMedGoogle Scholar
  45. 45.
    Christlieb AR. 1974. Renin, angiotensin and norepinephrine in alloxan diabetes. Diabetes, 23:962–970.PubMedGoogle Scholar
  46. 46.
    Kennefick TM, Oyama TT, Thompson MM, Vora JP, Anderson S. 1996. Enhanced renal sensitivity to angiotensin actions in diabetes mellitus in the rat. Am J Physiol, 271:F595–F602.Google Scholar
  47. 47.
    Ohishi K, Okwueze MI, Vari RC, Carmines PK. 1994. Juxtamedullary microvascular dysfunction during the hyperfiltration stage of diabetes mellitus. Am J Physiol, 267:F99–F105.Google Scholar
  48. 48.
    Blantz RC, Peterson OW, Gushwa L, Tucker BJ. 1982. Effect of modest hyperglycemia on tubuloglomerular feedback activity. Kidney Int, 22 (Suppl 12):S206–S212.Google Scholar
  49. 49.
    Vallon V, Blantz RC, Thomson S. 1995. Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats. Am J Physiol, 269:F876–F883.Google Scholar
  50. 50.
    Carmines PK, Ohishi K, Ikenaga H. 1996. Functional impairment of renal afferent arteriolar voltage-gated calcium channels in rats with diabetes mellitus. J Clin Invest, 98:2564–2571.CrossRefPubMedGoogle Scholar
  51. 51.
    Zhang PL, Mackenzie HS, Troy JL, Brenner BM 1994. Effects of an atrial natriuretic peptide receptor antagonist on glomerular hyperfiltration in diabetic rats. J Am Soc Nephrol, 4:1564–1570.PubMedGoogle Scholar
  52. 52.
    Jensen PK, Steven K, Blaehr H, Christiansen JS, Parving H-H. 1986. Effects of indomethacin on glomerular hemodynamics in experimental diabetes. Kidney Int, 29:490–495.CrossRefPubMedGoogle Scholar
  53. 53.
    Mayfield RK, Margolius HS, Levine JH, Wohltmann HJ, Loadholt CB, Colwell JA. 1984. Urinary kallikrein excretion in insulin-dependent diabetes mellitus and its relationship to glycemic control. J Clin Endocrinol Metab 59:278–286.CrossRefPubMedGoogle Scholar
  54. 54.
    Jaffa AA, Rust PF, Mayfield RK. 1995. Kinin, a mediator of diabetes-induced glomerular hyperfiltration. Diabetes, 44:156–160.CrossRefPubMedGoogle Scholar
  55. 55.
    Vora JP, Oyama TT, Thompson MM, Anderson S. 1997. Interactions of the kallikrein-kinin and renin-angiotensin systems in experimental diabetes. Diabetes, 46:107–112.CrossRefPubMedGoogle Scholar
  56. 56.
    Komers R, Cooper ME. 1995. Acute renal hemodynamic effects of ACE inhibition in diabetic hyperfiltration: role of kinins. Am J Physiol, 268:F588–F594.Google Scholar
  57. 57.
    Goldfarb S, Ziyadeh FN, Kern EFO, Simmons DA. 1991. Effects of polyol-pathway inhibition and dietary myo-inositol on glomerular hemodynamic function in experimental diabetes mellitus in rats. Diabetes, 40:465–471.CrossRefPubMedGoogle Scholar
  58. 58.
    Daniels BS, Hostetter TH. 1989. Aldose reductase inhibition and glomerular abnormalities in diabetic rats. Diabetes, 38:981–986.CrossRefPubMedGoogle Scholar
  59. 59.
    Andersons. 1993. Pharmacologic interventions in experimental animals. In Prevention of Progressive Chronic Renal Failure. El Nahas AM, Mallick NP, Anderson S, eds. Oxford: Oxford Univ. Press, 1993.Google Scholar
  60. 60.
    Kuchan MJ, Frangos JA 1993. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am J Physiol, 264:H150–H156.Google Scholar
  61. 61.
    Buga GM, Gold ME, Fukuto JM, Ignarro U. 1991. Shear stress-induced release of nitric oxide from endothelial cells grown on beads. Hypertension, 17:187–193.CrossRefPubMedGoogle Scholar
  62. 62.
    Awolesi MA, Sessa WC, Sumpio BE. 1995. Cyclic strain upregulates nitric oxide synthesis in cultured bovine aortic endothelial cells. J Clin Invest, 96:1449–1454.CrossRefPubMedGoogle Scholar
  63. 63.
    Ohno M, Cooke JC, Dzau VJ, Gibbons GH. 1995. Fluid shear stress induces endothelial tramforming growth factor beta-1 transcription and production. Modulation by potassium-channel blockade. J Clin Invest, 95:1363–1369.CrossRefPubMedGoogle Scholar
  64. 64.
    Nagel T, Resnick N, Atkinson WJ, Dewey CF, Jr, Gimbrone, MA, Jr. 1994. Shear stress selectively upregulates intercellular adhesion molecule-1 expression in cultured human vascular endothelial cells. J Clin Invest, 94:885–891.CrossRefPubMedGoogle Scholar
  65. 65.
    Ott MJ, Olsen JL, Ballermann BJ. 1995. Chronic in vitro flow promotes ultrastructural differentiation of endothelial cells. Endothelium 3:21–30.CrossRefGoogle Scholar
  66. 66.
    Malek AM, Gibbons GH, Dzau VJ, Izumo S. 1993. Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium. J Clin Invest 92:2013–2021.CrossRefPubMedGoogle Scholar
  67. 67.
    Riser BL, Cortes P, Zhao X, Bernstein J, Dumler F, Narins RG. 1992. Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat. J Clin Invest, 90:1932–1943.CrossRefPubMedGoogle Scholar
  68. 68.
    Yasuda T, Becker B, Kondo S, et al. 1994. Mechanical stretch/relaxation increases type 1 angiotensin II receptor expression and angjotensinogen mRNA in cultured rat mesangjal cells. J Am Soc Nephrol, 4:554, (abstr)Google Scholar
  69. 69.
    Harris RC, Haralson MA, Badr KF. 1992. Continuous stretch-relaxation in culture alters rat mesangial cell morphology, growth characteristics, and metabolic activity. Lab Invest, 66:548–554.PubMedGoogle Scholar
  70. 70.
    Riser BL, Cortes P, Heilig C, Grondin J, Ladson-Wofford S, Patterson D, Narins RG. Cyclic stretching force selectively up-regulates transforming growth factor-ß isoforms in cultured rat mesangial ells. Am J Pathol, 148:1915–1923.Google Scholar
  71. 71.
    Cortes P, Zhao X, Riser BL, Narins RG. 1997. Role of glomerular mechanical strain in the pathogenesis of diabetic nephropathy. Kidney Int, 51:57–68.CrossRefPubMedGoogle Scholar
  72. 72.
    Homma T, Akai Y, Burns KD, Harris RC. 1992. Activation of S6 kinase by repeated cycles of stretching and relaxation in rat glomerular mesangial cells. J Biol Chem, 267:23129–23135.PubMedGoogle Scholar
  73. 73.
    Yasuda T, Kondo S, Homma T, Harris RC. 1994. Mechanisms for accumulation of extracellular matrix in rat mesangial cells in response to stretch/relaxation. J Am Soc Nephrol, 4:824 (abstr)Google Scholar
  74. 74.
    Harris RC, Akai Y, Yasuda T, Homma T. 1995. The role of physical forces in alterations of mesangial cell function. Kidney Int 45 (Suppl 45):S17, 1995Google Scholar
  75. 75.
    Wagner CT, Durante W, Christodoulide N, Heliums JD, Schafer AI. 1997. Hemodynamic forces induce the expression of heme oxygenase in cultured vascular smooth muscle cells. J Clin Invest, 100:589–596.CrossRefPubMedGoogle Scholar
  76. 76.
    Ricardo SD, Ding G, Eufemio M, Diamond JR. 1997. Antioxidant expression in experimental hydronephrosis: role of mechanical stretch and growth factors. Am J Physiol, 272:F789–F798.Google Scholar
  77. 77.
    Mattana J, Singhal PC. 1995. Applied pressure modulates mesangial cell proliferation and matrix synthesis. Am J Hypertension, 8:1112–1120.CrossRefGoogle Scholar
  78. 78.
    Anderson S, Rennke HG, Garcia DL, Brenner BM. 1989. Short and long term effects of antihypertensive therapy in the diabetic rat. Kidney Int, 36:526–532.CrossRefPubMedGoogle Scholar
  79. 79.
    Anderson S, Rennke HG, Brenner BM. 1992. Nifedipine versus fosinopril in uninephrectomized diabeticrats. Kidney Int, 41:891–897.CrossRefPubMedGoogle Scholar
  80. 80.
    Cooper ME, Rumble JR, Allen T J, et al. 1992. Antihypertensive therapy and experimental diabetic nephropathy. Kidney Int, 41:898–903.CrossRefPubMedGoogle Scholar
  81. 81.
    Fujihara C, Padilha RM, Zatz R. 1992. Glomerular abnormalities in longterm experimental diabetes. Diabetes, 41:286–293.CrossRefPubMedGoogle Scholar
  82. 82.
    Geiger H, Bahner U, Vaaben W, et al. 1992. Effects of angiotensin-converting enzyme inhibition in diabetic rats with reduced renal function. J Lab Clin Med, 120:861–867.PubMedGoogle Scholar
  83. 83.
    O’Brien R, Cooper ME, Jerums G, Doyle AE. 1993. The effects of Perindopril and triple therapy in a normotensive model of diabetic nephropathy. Diabetes, 42:604–609.CrossRefPubMedGoogle Scholar
  84. 84.
    Brown SA, Walton CL, Crawford P, Bakris GL. 1993. Long-term effects of antihypertensive regjmens on renal hemodynamics and proteinuria. Kidney Int, 43:1210–1218.CrossRefPubMedGoogle Scholar
  85. 85.
    Anderson S, Jung FF, Ingelfinger JR. 1993. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biologic correlations. Am J Physiol, 265:F477–F486.Google Scholar
  86. 86.
    Remuzzi A, Perico N, Amuchastegui CS, Malanchini B, Mazerska M, Battaglia C, Bertani C, Remuzzi G. 1993. Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol, 4:40–49.PubMedGoogle Scholar
  87. 87.
    Wolf G, Ziyadeh N. 1997. The role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms. Am J Kidney Dis, 29:153–163.CrossRefPubMedGoogle Scholar
  88. 88.
    Kasiske BL, Kalil RSN, Ma JZ, Liao M, Keane WF. 1993. Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis. Ann Intern Med, 118:129–138.CrossRefPubMedGoogle Scholar
  89. 89.
    Böhlen L, de Courten M, Weidmann P. 1994. Comparative study of the effect of ACE-inhibitors and other antihypertensive agents on proteinuria in diabetic patients. Am J Hypertension, 7:84S–92S.Google Scholar
  90. 90.
    Lewis EJ, Hunsicker LG, Bain RP, Ronde RD. 1993. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. New Engl J Med, 329:1456–1462.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Sharon Anderson
    • 1
  1. 1.Division of Nephrology and HypertensionOregon Health Sciences UniversityPortlandUSA

Personalised recommendations