Transforming Growth Factor-Beta and other Cytokines in Experimental and Human Diabetic Nephropathy

  • Fuad N. Ziyadeh
  • Dong Cheol Han
  • Andras Mogyorosi


Increased renal extracellular matrix production in diabetes is most likely the result of increased synthesis and/or decreased degradation rates [1–3]. To model the effects of the diabetic milieu on the kidney, various renal cell lines have been investigated under high ambient glucose concentrations in tissue culture. High glucose stimulates proximal tubular cell hypertrophy [4] and modulates mesangial cell growth [5]. It also stimulates the production of connective tissue molecules such as fibronectin and collagens in proximal tubular cells and in glomerular mesangial, epithelial, and endothelial cells [4, 6–12]. It is noteworthy that periodically elevated glucose levels in rat mesangial cell culture increase collagen production to a greater extent than a sustained elevation in ambient glucose concentration [13]. This may closely mimic the fluctuations of blood glucose levels in vivo. The seminal factor for renal cell damage by high glucose is likely to be intracellular high glucose accumulation and metabolism rather than simply the extracellular, ambient hyperglycemia. Rat mesangial cells transfected with the human glucose transporter GLUTI gene demonstrate stimulated mesangial matrix synthesis despite physiologic extracellular glucose concentration [14].


Diabetic Nephropathy Mesangial Cell Proximal Tubular Cell Diabetic Kidney Disease Renal Hypertrophy 
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  1. 1.
    Ziyadeh FN: The extracellular matrix in diabetic nephropathy. Am J Kid Dis 22:736–744, 1993.PubMedGoogle Scholar
  2. 2.
    Ziyadeh FN: Renal tubular basement membrane and collagen type IV in diabetes mellitus. Kidney Ini 43:114–120, 1993.CrossRefGoogle Scholar
  3. 3.
    Cohen MP, and Ziyadeh FN: Role of Amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. J Am Soc Nephrol 7:1–8, 1996.Google Scholar
  4. 4.
    Ziyadeh FN, Snipes ER, Watanabe M, Alvarez RJ, Goldfarb S, and Haverty TP: High glucose induces cell hypertrophy and stimulates collagen gene transcription in proximal tubule. Am J Physiol 259:F704–F714, 1990.Google Scholar
  5. 5.
    Wolf G, Sharma K, Chen Y, Ericksen M, and Ziyadeh FN: High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-b. Kidney Int 42:647–656, 1992.PubMedCrossRefGoogle Scholar
  6. 6.
    Ayo SH, Radnik R, Garoni JA, and Kreisberg J: High glucose increases diacylglycerol mass and activates protein kinases C in mesangial cell culture. Am J Physiol 261:F571–F577, 1991.Google Scholar
  7. 7.
    Ayo SH, Radnik RA, Glass II WF, Garoni JA, Rampt ER, Appling DR, and Kreisberg JI: Increased extracellular matrix synthesis and mRNA in mesangial cells grown in high-glucose medium. Am J Physiol 260:F185–F191, 1991.Google Scholar
  8. 8.
    Haneda M, Kikkawa R, Horide N, Togawa M, Koya D, Kajiwara N, Ooshima A, and Shigeta Y: Glucose enhances type IV collagen production in cultured rat glomerular mesangial cells. Diabetologia 34:491–499, 1991.CrossRefGoogle Scholar
  9. 9.
    Ziyadeh FN, Sharma K, Ericksen M, and Wolf G: Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by activation of transforming growth factor-b. J Clin Invest 93:536–542, 1994.PubMedCrossRefGoogle Scholar
  10. 10.
    Wakisaka M, Spiro MJ, and Spiro RG: Synthesis of type VI collagen in cultured glomerular cells and comparison of its regulation by glucose and other factors with that of type IV collagen. Diabetes 43:95–103, 1994.CrossRefPubMedGoogle Scholar
  11. 11.
    Kolm V, Sauer U, Olgemoller B, and Schleicher ED: High glucose-induced TGF-b 1 regulates mesangial production of heparan sulfate proteoglycan. Am. J. Physiol 270:F812–F821, 1996.Google Scholar
  12. 12.
    van Det NF, Vemagen NAM, Tamsma JT, Berden JHM, Bruijn JA, Daha MR, and van der Woulde FJ: Regulation of glomerular epithelial cell production of fibronectin and transforming growth factor-b by high glucose, not by angiotensin II. Diabetes 46:834–840, 1997.PubMedCrossRefGoogle Scholar
  13. 13.
    Takeuchi A, Throckmorton DC, Brogden AP, Yoshizawa N, Rasmussen H, and Kashgarian M: Periodic high extracellular glucose enhances production of collagens III and IV by mesangial cells. Am J Physiol 268:F13–F19, 1995.Google Scholar
  14. 14.
    Heilig CW, Concepcion LA, Riser BL, and Freytag SO, Zhu M, Cortes P: Overexpression of glucose transporters in rat mesangial cells cultured in a normal glucose milieu mimics the diabetic phenotype. J Clin Invest 96: 1802–1814, 1995.PubMedCrossRefGoogle Scholar
  15. 15.
    van Det NF, van den Bom J, Tamsa JT, Vemagen NAM, Berden JHM, Brujin JA, Daha MR, and van der Woude F J: Effects of high glucose on the production of heparan sulfate proteoglycan by mesangial and epithelial cells. Kidney Int 49:1079–1089, 1996.PubMedCrossRefGoogle Scholar
  16. 16.
    Kasinath BS, Block JA, Singh AK, Terhune WC, Maldonado R, Davalath S, and Wanna L: Regulation of rat glomerular epithelial cell proteoglycans by high-medium glucose. Arch of Biochem and Biophys 309:149–159, 1994.CrossRefGoogle Scholar
  17. 17.
    Sharma K, and Ziyadeh FN: Biochemical events and cytokine interactions linking glucose metabolism to the development of diabetic nephropathy. Semin Nephrol 17:80–92, 1997.PubMedGoogle Scholar
  18. 18.
    Wolf G, and Ziyadeh FN: The role of angiotensin II in diabetic nephropathy: Emphasis on nonhemodynamic mechanisms. Am J Kidney Dis 29:153–163, 1997.PubMedCrossRefGoogle Scholar
  19. 19.
    Hoflman BB, and Ziyadeh FN: The role of growth factors in the development of diabetic nephropathy. Curr Opin Endocrin Diabetes 3:322–329, 1996.CrossRefGoogle Scholar
  20. 20.
    Abboud HE: Growth factors and diabetic nephropathy:an overview. Kidney Int 52(suppl 60):S3–6, 1997.CrossRefGoogle Scholar
  21. 21.
    Roberts AB, McCune BK, and Sporn MB: TGF-b: Regulation of extracellular matrix. Kidney Int 41:557–559, 1992.PubMedCrossRefGoogle Scholar
  22. 22.
    MacKay K, Kondiah P, Danielpour D, Austin HA, and Brown PD: Expression of transforming growth factor-bl and b2 in rat glomeruli. Kidney Int 38:1095–1100, 1990.PubMedCrossRefGoogle Scholar
  23. 23.
    Roberts AB, Kim S-J, Noma T, Glick AB, Lafyatis R, Lechleider R, Jaakowlew SB, Geiser A, O’Reilly MA, Danielpour D, and Spom MB. 1991. Multiple forms of TGF-b: distinct promoters and differential expression. In Clinical Applications of TGF-b. M. B. Spom and A. B. Roberts, eds. Ciba Foundation Symposium, Chichester, U.K. p. 7–28.Google Scholar
  24. 24.
    Miyazano K, and Heldin C-H, ed. Latent forms of TGF-b: Molecular structure and mechanisms of activation. Clinical Application of TGF-b., G. R. Bock and J. Marsh, eds. 1991, Wiley, Chichester, UK. p. 81–92.Google Scholar
  25. 25.
    Paralkar VM, Vukicewic S, and Reddi AH: Transforming growth factor b type 1 binds to collagen IV of basement membrane matrix: implications for development Dev Biol 143:303–308, 1991.PubMedCrossRefGoogle Scholar
  26. 26.
    Wakefield LM, Winokur TS, Hollands RS, Christopherson K, Levinson AD, and Sporn MB: Recombinant latent transforming growth factor bl has a longer half-life in rats than active transforming growth factor bl, and a différent tissue distribution. J Clin Invest 86:1976–1984, 1990.PubMedCrossRefGoogle Scholar
  27. 27.
    Flaumenhaft R, Abe M, Mignatti P, and Rifkin DB: Basic fibroblast growth factor-induced activation of latent transforming growth factor-b in endothelial cells: regulation of plasminogen activator activity. J Cell Biol 118:901–909, 1992.PubMedCrossRefGoogle Scholar
  28. 28.
    Ando T, Okuda S, Tamaki K, Yoshitomi K, and Fujishima M: Localization of transforming growth factor-b and latent transforming growth factor-b binding protein in rat kidney. Kidney Int 47:733–739, 1995.PubMedCrossRefGoogle Scholar
  29. 29.
    Massague J, Attisano L, and Wrana JL: The TGF-b family and its composite receptors. Trends CellBiol 4:172–178, 1994.CrossRefGoogle Scholar
  30. 30.
    Wrana JL, Attisano L, Wieser R, Ventura F, and Massague J: Mechanism of activation of the TGF-b receptor. Nature 370:341–347, 1994.PubMedCrossRefGoogle Scholar
  31. 31.
    Wieser R, Attisano L, Wrana JL, and Massague J: Signaling activity of transforming growth factor b type II receptors lacking specific domains in the cytoplasmic region. Mol Cell Biol 7239–7247, 1993.Google Scholar
  32. 32.
    Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, and Gelbart WM: Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139:1347–1358, 1995.PubMedGoogle Scholar
  33. 33.
    Liu F, Hata A, Baker JC, Doody J, Carcamo J, Harland RM, and Massague J: A human Mad protein acting as a BMP-regulated transcriptional activator. Nature 381.620–623, 1996.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhang Y, Feng X, We R, and Derynck R: Receptor-associated Mad homologues synergize as effectors of the TGF-b response. Nature 383:168–172, 1996.PubMedCrossRefGoogle Scholar
  35. 35.
    Hayashi H, Abdollah S, Qiu Y, Cai J, Xu Y, Grirmell BW, Richardson MA, Topper JN, Gimbrone MA, Wrana JL, and Falb D: The MAD-related protein Smad7 associates with the TGF-b receptor and functions as an antagonist of TGF-b signaling. Cell 89:1165–1173, 1997.PubMedCrossRefGoogle Scholar
  36. 36.
    Laiho M, Saksela O, Andreasen PA, and Keski-Oja J: Enhanced production and extracellular deposition of the endothelial-type plasminogen activator inhibitor in cultured human lung fibroblasts by transforming growth factor-beta. J Cell Biol 103:2403–2410, 1986.PubMedCrossRefGoogle Scholar
  37. 37.
    Ziyadeh FN, Simmons DA, Snipes ER, and Goldfarb S: Effect of myo-inositol on cell proliferation and collagen transcription and secretion in proximal tubule cells cultured in elevated glucose. J Am SocNephrot 1:1220–1229, 1991.Google Scholar
  38. 38.
    Rocco M, Chen Y, Goldfarb S, and Ziyadeh FN: Elevated glucose stimulates TGF-b gene expression and bioactivity in proximal tubule. Kidney Int. 41:107–114, 1992.PubMedCrossRefGoogle Scholar
  39. 39.
    Di Paolo S, Gesualdo L, Ranieri E, Grandaliano G, and Schena FP: High glucose concentration induces the overexpression of transforming growth factor-b through the activation of a platelet-derived growth factor loop in human mesangial cells. Am J Path 149:2095–2106, 1996PubMedGoogle Scholar
  40. 40.
    Phillips AO, Steadman R, Topley N, and Williams JD: Elevated D-glucose concentrations modulate TGF-beta 1 synthesis by human cultured renal proximal tubular cells. The permissive role of platelet-derived growth factor. Am J Pathol 147:362–374, 1995.PubMedGoogle Scholar
  41. 41.
    Mogyorosi A, Hoffman BB, Guo J, Jin Y, Ericksen M, Sharma K, and Ziyadeh FN: Elevated glucose concentration stimulates expression of the type II receptor in glomerular mesangial cells, (abstract). J. AM. Soc. Nephrol 7:1875, 1996.Google Scholar
  42. 42.
    Guh JY, Yang ML, Yanf YY, Chang CC, and Chuang LY: Captopril reverses high-glucose induced growth effects on LLC-PK1 cells partly by decreasing transforming growth factor-b receptor protein expression. J. AM. Soc. Nephrol. 7:1207–1215, 1996.PubMedGoogle Scholar
  43. 43.
    Song RH, Singh AK, Alavi N, and Leehey DJ: Decreased collagenase activity of mesangial cells incubated in high glucose media is reversed by neutralizing antibody to transforming growth factor beta. J Am Soc Neph 5:972 (abstract), 1994.Google Scholar
  44. 44.
    Sharma K, and Ziyadeh FN: Hyperglycemia and diabetic kidney disease: the case for transforming growth factor-b as a key mediator. Diabetes 44:1139–1146, 1995.PubMedCrossRefGoogle Scholar
  45. 45.
    Park I-S, Kiyomoto H, Abboud S, and Abboud H: Expression of transforming growth factor-b and type IV collagen in early streptozotocin-induced diabetes. Diabetes 46:473–480, 1997.PubMedCrossRefGoogle Scholar
  46. 46.
    Sharma K, and Ziyadeh FN: Renal hypertrophy is associated with upregulation of TGF-b1 gene expression in diabetic BB rat and NOD mouse. Am J Physiol 267:F1094–F1101, 1994.Google Scholar
  47. 47.
    Sharma K, Guo J, Jin Y, and Ziyadeh FN: Neutralization of TGF-b by anti-TGF-b antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45:522–530, 1996.PubMedCrossRefGoogle Scholar
  48. 48.
    Pankewycz OG, Guan JX, Bolton WK, Gomez A, and Benedict JF: Renal TGF-beta regulation in spontaneously diabetic NOD mice with correlations in mesangial cells. Kidney Int 46:748–58, 1994.PubMedCrossRefGoogle Scholar
  49. 49.
    Shankland SJ, and Scholey JW: Expression of transforming growth factor-b 1 during diabetic renal hypertrophy. Kidney Int 46:430–442, 1994.PubMedCrossRefGoogle Scholar
  50. 50.
    Yang S, Fletcher WH, and Johnson DA: Regulation of cAMP-dependent protein kinase: enzyme activation without dissociation. Biochem 34:6267–6271, 1995.CrossRefGoogle Scholar
  51. 51.
    Koya D, M. R. J, Lin Y-W, Ishii H, Kuboki K, and King GL: Characterization of protein kinase beta isoform activation on the gene expression of transforming growth factor-b, extracelluar matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Med 100:115–126, 1997.Google Scholar
  52. 52.
    Reckelhoff JF, tygart VL, Mitias MM, and Walcott JL: STZ-inducted diabetes results in decreased activity of glomerular cathepsin and metalloprotease in rats. Diabetes 42:1425–1432, 1993.PubMedCrossRefGoogle Scholar
  53. 53.
    Yamamoto T, Nakamura T, Noble NA, Ruoslahti E, and Border WA: Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci USA 90:1814–1818, 1993.PubMedCrossRefGoogle Scholar
  54. 54.
    Nakamura T, Fukui M, Ebihara I, Osada S, Nagaoka I, Tomino Y, and Koide H: mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 42:450–456, 1993.PubMedCrossRefGoogle Scholar
  55. 55.
    Bertoluci MC, Schmid H, Lachat J-J, and Coimbra TM: Transforming growth factor-beta in the development of rat diabetic nephropathy- a 10 month study with insulin-treated rats. Nephron 74:189–196, 1996.PubMedCrossRefGoogle Scholar
  56. 56.
    Han DC, Kim YJ, Cha MK, Song KI, Kim JH, Lee EY, Ha H, and Lee HB: Glucose control suppressed the glomerular expression of TGF-b1 and the progression of experimental diabetic nephropathy. J Am Soc Nephrol 7:1870 (abstract), 1996.Google Scholar
  57. 57.
    Yamamoto T, Noble NA, Cohen AH, Nast CC, Hishida A, Gold LI, and Border WA: Expression of transforming growth factor-b isoforms in human glomerular diseases. Kidney Int 49:461–469, 1996.PubMedCrossRefGoogle Scholar
  58. 58.
    Yoshioka K, Takemura T, Murakami K, Okada M, Hino S, Miyamoto H, and Maki S: Transforming growth factor-b protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest 68:154–163, 1993.PubMedGoogle Scholar
  59. 59.
    Iwano M, Atsushi K, Nishino T, Sato H, Nishioka H, Akai Y, Kurioka H, Fuji Y, Kanauchi M, Shiiki H, and Dohi K: Quantification of glomerular TGF-bl mRNA in patients with diabetes mellitus. Kidney Int 49:1120–1126, 1996.PubMedCrossRefGoogle Scholar
  60. 60.
    Sharma K, Ziyadeh FN, Alzahabi B, McGowan TA, Kapoor S, Kumik BRC, Kumik PB, and Weisberg LS: Increased renal production of transforming growth factor-b 1 in patients with type II diabetes. Diabetes 46:854–859, 1997.PubMedCrossRefGoogle Scholar
  61. 61.
    Fukui M, Nakamura T, Ebihara I, Makita Y, Osada S, Tomino Y, and Koide H: Effects of enalapril on endothelin-1 and growth factor expression in diabetic rat glomeruli. J Lab Clin Med 123:763–768, 1994.PubMedGoogle Scholar
  62. 62.
    Inaba T, Ishibashi S, Gotoda T, Kawamura M, Morino N, Nojima Y, Kawakami M, Yazaki Y, and Yamada N: Enhanced expression of platelet derived growth factor- beta receptor by high glucose: involvement of platelet derived growth factor in diabetic angiopathy. Diabetes 45:507–512, 1996.PubMedCrossRefGoogle Scholar
  63. 63.
    Throckmorton DC, Brogden AP, Min B, Rasmussen H, and Kashgarian M: PDGF and TGF-b mediate collagen production by mesangial cells exposed to advanced glycation end products. Kidney Int 48:111–117, 1995.PubMedCrossRefGoogle Scholar
  64. 64.
    Doi TT, Vlassara H, Kirstein M, Yamada Y, Striker GE, and Striker L: Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Pro Natl Acad Sci USA 89:2873–2877, 199Google Scholar
  65. 65.
    Morabito E, Corsico N, and Arrigoni Martelli E: Endothelins urinary excretion in spontaneously diabetic rats: BB/BB. Life Sciences 56:13–18, 1995.Google Scholar
  66. 66.
    Nakamura T, Ebihara I, Fukui M, Tomino Y, and Koide H: Effect of a specific endothelin receptor A antagonist on mRNA levels for extracellular matrix components and growth factors in diabetic glomeruli. Diabetes 44:895–899, 1995.PubMedCrossRefGoogle Scholar
  67. 67.
    Takahashi K, Ghatei MA, Lam H-C, O’halloran DJ, and Bloom SR: Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 33:306–310, 1990.PubMedCrossRefGoogle Scholar
  68. 68.
    Ferri C, Laurenti O, Bellini C, Faldetta MRC, Properzi G, Santucci A, and De Mattia G: Circulating endothelin-1 levels in lean non-insulin-dependent diabetic patients. Am J Hypertens 8:40–47, 1995.PubMedCrossRefGoogle Scholar
  69. 69.
    Wolf G, Mueller E, Stahl RAK, and Ziyadeh FN: Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells by endogenous TGF-b. J Clin Invest 92:1366–1373, 1993.PubMedCrossRefGoogle Scholar
  70. 70.
    Kagami S, Border WA, Miller DE, and Noble NA: Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-b expression in rat glomerular mesangial cells. J Clin Invest 93:2431–2437, 1994.PubMedCrossRefGoogle Scholar
  71. 71.
    Lewis EJ, Hunsicker LG, Bain RP, and Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 329:1456–1462, 1993.PubMedCrossRefGoogle Scholar
  72. 72.
    Mogensen CE: Renoprotective role of ACE inhibitors in diabetic nephropathy. Br Heart J 72:S38–45, 1994.CrossRefGoogle Scholar
  73. 73.
    Ledbetter S, Copeland EJ, Noonan D, Vogeli G, and Hassell JR: Altered steady-state mRNA levels of basement membrane proteins in diabetic mouse kidneys and thromboxane synthase inhibition. Diabetes 39:196–203, 1990.PubMedCrossRefGoogle Scholar
  74. 74.
    Craven PA, Caines MA, and DeRubertis FR: Sequential alterations in glomerular prostaglandin and thromboxane synthesis in diabetic rats: Relationship to the hyperfiltration of early diabetes. Metabolism 36:95–103, 1987.PubMedCrossRefGoogle Scholar
  75. 75.
    Craven PA, and DeRubertis FR: Protein kinase C is activated in glomeruli from streptozotocin diabetic rats. J Clin Invest 83:1667–1675, 1989.PubMedCrossRefGoogle Scholar
  76. 76.
    Gambardella S, Andreani D, Cancelli A, DiMario U, Cardamone I, Stirats G, Cinotti GA, and Pugliese F: Renal hemodynamics and urinary excretion of 6-keto prostaglandin F la, and thromboxane B2 in newly diagnosed type I diabetic patients. Diabetes 37:1044–1048, 1988.PubMedCrossRefGoogle Scholar
  77. 77.
    Craven PA, Meinem MF, and DeRubertis FR: Thromboxane in the pathogenesis of glomerular injury in diabetes. Kidney Int 42:937–946, 1992.PubMedCrossRefGoogle Scholar
  78. 78.
    DeRubertis FR, and Craven PA: Contribution of platelet thromboxane production to enhanced urinary excretion and glomerular production of thromboxane and to the pathogenesis of albuminurira in the streptozotocin-diabetic rat. Metabolism 41:90–96, 1992.PubMedCrossRefGoogle Scholar
  79. 79.
    Bruggeman LA, Horigan EA, Horikoshi S, Ray PE, and Klotman PE: Thromboxane stimulates synthesis of extracellular matrix proteins in vitro. Am J Physiol 261:F488–F494, 1991.Google Scholar
  80. 80.
    Studer RK, Negrete H, Craven PA, and DeRubertis FR: Protein kinase C signals thromboxane induced increases in fibronectm synthesis and TGF-beta bioactivity in mesangial cells. Kidney Int 48:422–430, 1995.PubMedCrossRefGoogle Scholar
  81. 81.
    Matsuo Y, Takagawa I, Koshida H, Kawabata T, Nakamura M, Ida T, Zhou L, and Marumo F: Antiproteinuric effect of a thromboxane receptor antagonist, S-1452, on rat diabetic nephropathy and murine lupus nephritis. Pharmacology 50:1–8, 1995.PubMedCrossRefGoogle Scholar
  82. 82.
    Hora K, Oguchi H, Furakawa T, Hora K, and Tokunaga S: Effects of a selective thromboxane synthetase inhibitor OKY-046 on experimental diabetic nephropathy. Nephron 56:297–305, 1990.PubMedCrossRefGoogle Scholar
  83. 83.
    Pricci E, Pugliese G, Mene P, Romeo G, Galli G, Casini A, Rotella CM, Di Mario U, and Pugliese F: Regulatory role of eicosanoids in extracellular matrix overproduction induced by long-term exposure to high glucose in cultured rat mesangial cells. Diabetologia 39:1055–1062, 1996.PubMedCrossRefGoogle Scholar
  84. 84.
    Flyvbjerg A, Bornfeldt KE, Marshall SM, Amqvist HJ, and Orskov H: Kidney IGF-I mRNA in initial renal hypertrophy in experimental diabetes in rats. Diabetologia 33:334–338, 1990.PubMedCrossRefGoogle Scholar
  85. 85.
    Flyvbjerg A, Marshall SM, Frystyk J, Hansen KW, Harris AG, and Orskov H: Octreotide administration in diabetic rats: Effect on renal hypertrophy and urinary albumin excretion. Kidney Int. 41:805–812, 1992.PubMedCrossRefGoogle Scholar
  86. 86.
    Serri O, Beauregard H, Brazeau P, Abribat T, Lambert J, Harris A, and Vachon L: Somatostatin analogue, octreotide, reduces increased glomerular filtration rate and kidney size in insulin-dependent diabetes. JAMA 265:888–892, 1991.PubMedCrossRefGoogle Scholar
  87. 87.
    Quaife C, Mathews L, Pinkert C, Hammer R, Brinster R, and Palmiter R: Histopathology associated with elevated levels of growth hormone and insulin-like growth factor I in transgenic mice. Endocrinology 124:40–48, 1989.PubMedCrossRefGoogle Scholar
  88. 88.
    Goldfarb S, Ziyadeh FN, Kern EFO, and Simmons DA: Effects of polyol-pathway inhibition and dietary myoinositol on glomerular hemodynamic function in experimental diabetes mellitus in rats. Diabetes 40:465–471, 1991.PubMedCrossRefGoogle Scholar
  89. 89.
    DeRubertis FR, and Craven P: Activation of protein kinase C in glomerular cells in diabetes: mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 43:1–8, 1994.PubMedCrossRefGoogle Scholar
  90. 90.
    Fumo P, Kuncio GS, and Ziyadeh FN: PKC and high glucose stimulate collagen al(IV) transcriptional activity in a reporter mesangial cell line. Am J Physiol In Press, 1994.Google Scholar
  91. 91.
    Brownlee M, Vassara H, and Cerami A: Nonenzymatic glycosylation and the pathogensis of diabetes complications. Ann Int Med 101:527–537, 1984.PubMedCrossRefGoogle Scholar
  92. 92.
    Cohen MP, and Ziyadeh FN: Amadori glucose adducts modulate mesangial cell growth and collagen gene expression. Kidney Int 45:475–484, 1994.PubMedCrossRefGoogle Scholar
  93. 93.
    Hoffman B, Sharma K, Ericksen M, and Ziyadeh F: Transcriptional activation of TGF-b1 by high glucose. J. Am. Soc. Nephrol 6:1041(abstract), 1995.Google Scholar
  94. 94.
    Kim S-J, Glick A, Spom MB, and Roberts AB: Characterization of the promoter region of the human transforming growth factor-b1 gene. J Biol Chem 264:402–408, 1989.PubMedGoogle Scholar
  95. 95.
    Negrete H, Studer RK, Craven PA, and DeRubertis FR: Role for transforming growth factor beta in thromboxane-induced increases in mesangial cell fibronectin synthesis. Diabetes 44:335–339, 1995.PubMedCrossRefGoogle Scholar
  96. 96.
    Zhang G, Kazanietz MG, Blumberg PM, and Hurley JH: Crystal structure of the Cys2 activator-binding domain of protein kinase δ in complex with phorbol ester. Cell 81:917–924, 1995.PubMedCrossRefGoogle Scholar
  97. 97.
    Haneda M, Araki S, Togawa M, Sugimoto T, Isono M, and Kikkawa R: Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells under high glucose conditions. Diabetes 46:847–853, 1997.PubMedCrossRefGoogle Scholar
  98. 98.
    de Groot RP, Auwerx J, Karperien M, Staels B, and Kruijer W: Activation of JunB by PKC and PKA sigpal transduction through a novel cis-acting element. Nucleic Acids Res 19:775–781, 1991.PubMedCrossRefGoogle Scholar
  99. 99.
    Chung KY, Agarwal A, Uitto J, and Mauviel A: An AP-1 binding sequence is essential for regulation of the human a2(I) collagen promoter activity by transforming growth factor-b. J Biol Chem 271:3272–3278, 1996.PubMedCrossRefGoogle Scholar
  100. 100.
    Shankland SJ, and Scholey JW: Expression of growth-related protooncogenes during diabetic renal hypertrophy. Kidney Int 47:782–788, 1995.PubMedCrossRefGoogle Scholar
  101. 101.
    Kim S-J, Angel P, Lafyatis R, Hattori K, Kim KY, Sporm MB, Karin M, and Roberts AB: Autoinduction of Transforming Growth facor b1 is mediated by the AP-1 complex. Mol Cell Biol 10:1492–1497, 1990.PubMedGoogle Scholar
  102. 102.
    Ziyadeh FN, Mogyorosi A, and Kalluri R: Early and Advanced Nonenzymatic glycation products in the pathogenesis of diabetic kidney disease. Exp Nephrol 5:2–9, 1997.PubMedGoogle Scholar
  103. 103.
    Yang C-W, Vlassara H, Peten EP, He C-J, Striker GE, and Striker LJ: Advanced glycation end products up-regulate gene expression found in diabetic glomerular disease. Proc Natl Acad of Sci, USA 91:9436–9440, 1994.CrossRefGoogle Scholar
  104. 104.
    Ha H, Kamanna VS, Kirschenbaum MA, and Kim KH: Role of glycated low density lipoprotein in mesangial extracellular matrix synthesis. Kidney Int 52 (suppl 60):s54- s59, 1997.Google Scholar
  105. 105.
    Skolnik EY, Yang Z, Makita Z, Radoff S, Kirstein M, and Vlassara H: Human and rat mesangial cell receptors for glucose-modified proteins: potential role in kidney tissue remodelling and diabetic nephropathy. J Exp Med 174:931–939, 1991.PubMedCrossRefGoogle Scholar
  106. 106.
    Riser BL, Cortes P, Zhao X, Bernstein J, Dumier F, and Narins RG: Intraglomerular pressure and mesangial stretching stimulate extracellular matrix formation in the rat. J Clin Invest 90:1932–1943, 1992.PubMedCrossRefGoogle Scholar
  107. 107.
    Yasuda T, Satoshi K, Homma T, and Harris RC: Regulation of extracellular matrix by mechanical stress in rat glomerular mesangial cells. J Clin Invest 98:1991–2000, 1996.PubMedCrossRefGoogle Scholar
  108. 108.
    Riser BL, Cortes P, Heilig C, Grondin J, Ladsonwofford S, Patterson D, and Narins RG: Cyclic stretching force selectively up-regulates transforming growth factor-beta isoforms in cultured rat mesangial cells. Am J Pathol 148:1915–1923, 1996.PubMedGoogle Scholar
  109. 109.
    Ohno M, Cooke JP, Dzau V, J., and Gibbons GH: Fluid shear stress induces endothelial transforming growth factor b-1 transcription and production. Modulation by potassium channel blckade. J Clin Invest 95:1363–1369, 1995.PubMedCrossRefGoogle Scholar
  110. 110.
    Mogensen CE, and Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311:89–93, 1984.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1998

Authors and Affiliations

  • Fuad N. Ziyadeh
    • 1
  • Dong Cheol Han
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  • Andras Mogyorosi
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  1. 1.Penn Center for Molecular Studies of Kidney Diseases, Renal Electrolyte and Hypertension Division, Department of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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