Seminars in Nephrology
Volume 27, Issue 2 , Pages 153-160 , March 2007

Regulation of Transforming Growth Factor β in Diabetic Nephropathy: Implications for Treatment

  • Yanqing Zhu, MD
    • ,
  • Hitomi Kataoka Usui, MD, PhD
    • ,
  • Kumar Sharma, MD

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Kumar Sharma, MD, Thomas Jefferson University, Suite 353, Jefferson Alumni Hall, 1020 Locust St, Philadelphia, PA 19107.

References 

  1. Sharma K, Ziyadeh F. Biochemical events and cytokine interactions linking glucose metabolism to the development of diabetic nephropathy. Semin Nephrol. 1997;17:80–92
  2. McGowan T, Zhu Y, Sharma K. Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy. Curr Diabetes Rep. 2004;4:447–454
  3. McGowan TA, Dunn SR, Falkner B, Sharma K. Stimulation of urinary TGF-{beta} and isoprostanes in response to hyperglycemia in humans. Clin J Am Soc Nephrol. 2006;1:263–268
  4. Whiteside C, Dlugosz JA. Mesangial cell protein kinase C isozyme activation in the diabetic milieu. Am J Physiol. 2002;282:F975–F980
  5. Studer RK, Craven PA, DeRubertis FR. Role for protein kinase C in the mediation of increased fibronectin accumulation by mesangial cells grown in high glucose medium. Diabetes. 1993;42:118–126
  6. Lee TS, Saltsman KA, Ohashi H, King GL. Activation of protein kinase C by elevation of glucose concentration: proposal for a mechanism in the development of diabetic vascular complications. Proc Natl Acad Sci U S A. 1989;86:5141–5145
  7. Koya D, Jirousek M, Lin Y, Ishii H, Kuboki K, King G. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest. 1997;100:115–126
  8. Koya D, Haneda M, Nakagawa H, Isshiki K, Sato H, Maeda S, et al. Amelioration of accelerated diabetic mesangial expansion by treatment with a PKC beta inhibitor in diabetic db/db mice, a rodent model for type 2 diabetes. FASEB J. 2000;14:439–447
  9. Tuttle KR, Bakris GL, Toto RD, McGill JB, Hu K, Anderson PW. The effect of ruboxistaurin on nephropathy in type 2 diabetes. Diabetes Care. 2005;28:2686–2690
  10. Menne J, Park J-K, Boehne M, Elger M, Lindschau C, Kirsch T, et al. Diminished loss of proteoglycans and lack of albuminuria in protein kinase c-{alpha}--deficient diabetic mice. Diabetes. 2004;53:2101–2109
  11. Hua H, Munk S, Goldberg H, Fantus IG, Whiteside CI. High glucose-suppressed endothelin-1 Ca2+ signaling via NADPH oxidase and diacylglycerol-sensitive protein kinase C isozymes in mesangial cells. J Biol Chem. 2003;278:33951–33962
  12. Iglesias-De La Cruz MC, Ruiz-Torres P, Alcami J, Diez-Marques L, Ortega-Velazquez R, Chen S, et al. Hydrogen peroxide increases extracellular matrix mRNA through TGF-beta in human mesangial cells. Kidney Int. 2001;59:87–95
  13. Nath KA, Grande J, Croatt A, Haugen J, Kim Y, Rosenberg ME. Redox regulation of renal DNA synthesis, transforming growth factor-[bgr]1 and collagen gene expression. Kidney Int. 1998;53:367
  14. Melhem MC, Liachenko J, DeRubertis FR. Alpha-lipoic acid attenuates hyperglycemia and prevents glomerular mesangial matrix expansion in diabetes. J Am Soc Nephrol. 2002;13:108–116
  15. DeRubertis F, Craven P, Melhem M, Salah E. Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction. Diabetes. 2004;53:762–768
  16. Gorin Y, Block K, Hernandez J, Bhandari B, Wagner B, Barnes JL, et al. Nox4 NAD(P)H oxidase mediates hypertrophy and fibronectin expression in the diabetic kidney. J Biol Chem. 2005;280:39616–39626
  17. Thannickal VJ, Fanburg BL. Activation of an H2O2-generating NADH oxidase in human lung fibroblasts by transforming growth factor B1*. J Biol Chem. 1995;270:30334–30338
  18. Hu T, Ramachandrarao SP, Siva S, Valancius C, Zhu Y, Mahadev K, et al. Reactive oxygen species production via NADPH oxidase mediates TGF-{beta}-induced cytoskeletal alterations in endothelial cells. Am J Physiol. 2005;289:F816–F825
  19. Sharma K, Cook A, Smith M, Valancius C, Inscho EW. TGF-{beta} impairs renal autoregulation via generation of ROS. Am J Physiol. 2005;288:F1069–F1077
  20. Yamamoto S. Mammalian lipoxygenases: molecular structures and functions. Biochim Biophys Acta. 1992;1128:117–131
  21. Leonarduzzi G, Scavazza A, Biasi F, Chiarpotto E, Camandola S, Vogel S, et al. The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor beta1 expression in the macrophage lineage: a link between oxidative injury and fibrosclerosis. FASEB J. 1997;11:851–857
  22. Reddy M, Adler SG, Kim YS, Lanting L, Rossi J, Kang SW, et al. Interaction of MAPK and 12-lipoxygenase pathways in growth and matrix protein expression in mesangial cells. Am J Physiol. 2002;283:F985–F994
  23. Kim Y-S, Xu Z-G, Reddy MA, Li S-L, Lanting L, Sharma K, et al. Novel interactions between TGF-{beta}1 actions and the 12/15-lipoxygenase pathway in mesangial cells. J Am Soc Nephrol. 2005;16:352–362
  24. Nerlich A, Sauer U, Kolm-Litty V, Wagner E, Koch M, Schleicher ED, et al. Expression of glutamine:fructose-6-phosphate amidotransferase in human tissues: evidence for high variability and distinct regulation in diabetes. Diabetes. 1998;47:170–178
  25. Kolm-Litty V, Sauer U, Nerlich A, Lehmann R, Schleicher E. High glucose-induced transforming growth factor-β1 production is mediated by the hexosamine pathway in procine glomerular mesangial cells. J Clin Invest. 1998;101:160–169
  26. Burt D, Gruden G, Thomas SM, Tutt P, Dell’Anna C, Viberti GC, et al. p38 mitogen-activated protein kinase mediates hexosamine-induced TGFbeta1 mRNA expression in human mesangial cells. Diabetologia. 2003;46:531–537
  27. Haneda M, Koya D, Kikkawa R. Cellular mechanisms in the development and progression of diabetic nephropathy: activation of the DAG-PKC-ERK pathway. Am J Kidney Dis. 2001;38(Suppl 1):S178–S181
  28. Kang HS, Adler S, LaPage J, Natarajan R. p38 MAPK and MAPK kinase 3/6 mRNA mRNA and activities are increased in early diabetic glomeruli. Kidney Int. 2001;60:543–552
  29. Feliers D, Duraisamy S, Faulkner JL, Duch J, Lee AV, Abboud H, et al. Activation of renal signaling pathways in db/db mice with type 2 diabetes. Kidney Int. 2001;60:495–504
  30. Haneda M, Araki S, Togawa M, Sugimoto T, Isono M, Kikkawa R. Mitogen-activated protein kinase cascade is activated in glomeruli of diabetic rats and glomerular mesangial cells cultured under high glucose conditions. Diabetes. 1997;46:847–853
  31. Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC, et al. Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia. 2004;47:1210–1222
  32. Zhang M, Fraser D, Phillips A. ERK, p38, and smad signaling pathways differentially regulate transforming growth factor-{beta}1 autoinduction in proximal tubular epithelial cells. Am J Pathol. 2006;169:1282–1293
  33. Guha M, Bai W, Nadler JL, Natarajan R. Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways. J Biol Chem. 2000;275:17728–17739
  34. Wilmer W, Dixon C, Herbert C. Chronic exposure to high glucose environment activates the p38 MAPK pathway. Kidney Int. 2001;60:858–871
  35. Kuki S, Imanishi T, Kobayashi K, Matsuo Y, Obana M, Akasaka T. Hyperglycemia accelerated endothelial progenitor cell senescence via the activation of p38 mitogen activated protein kinase. Circulation J. 2006;70:1076–1081
  36. Dai T, Natarajan R, Nast C, LaPage J, Chuang P, Sim J, et al. Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton. Kidney Int. 2006;69:806–814
  37. Wada TAH, Furuichi K, Sakai N, Kitagawa K, Iwata Y, Matsushima K, et al. Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase. Am J Nephrol. 2006;26:319–325
  38. Weigert C, Sauer U, Brodbeck K, Pfeiffer A, Haring H, Schleicher ED. AP-1 proteins mediate hyperglycemia-induced activation of the human TGF-b1 promoter in mesangial cells. J Am Soc Nephrol. 2000;11:2007–2016
  39. Geiser AG, Kim S-J, Roberts AB, Sporn MB. Characterization of the mouse transforming growth factor-b1 promoter and activation by the Ha-ras oncogene. Mol Cell Biol. 1991;11:84–92
  40. Suresh BP, Srinivasan K. Amelioration of renal lesions associated with diabetes by dietary curcumin in streptozotocin diabetic rats. Mol Cell Biochem. 1998;181:87–96
  41. Sharma S, Kulkarni SK, Chopra K. Curcumin, the active principle of turmeric (curcuma longa), ameliorates diabetic nephropathy in rats. Clin Exp Pharmacol Physiol. 2006;33:940–945
  42. Hoffman B, Sharma K, Zhu Y, Ziyadeh FN. Transcriptional activation of transforming growth factor-b1 in mesangial cell culture by high glucose concentration. Kidney Int. 1998;54:1107–1116
  43. Zhu Y, Casado M, Vaulont S, Sharma K. Role of upstream stimulatory factors in regulation of renal transforming growth factor-{beta}1. Diabetes. 2005;54:1976–1984
  44. Weigert C, Brodbeck K, Sawadogo M, Haring HU, Schleicher ED. Upstream stimulatory factor (USF) proteins induce human TGF-{beta}1 gene activation via the glucose-response element-1013/-1002 in mesangial cells: up-regulation of USF activity by the hexosamine biosynthetic pathway. J Biol Chem. 2004;279:15908–15915
  45. In:  Miyazano K,  Heldin C-H editor. Latent forms of TGF-b: molecular structure and mechanisms of activation. Chichester, UK: Wiley; 1991;p. 81–92
  46. Roberts AB. TGF-beta signaling from receptors to the nucleus. Microbes Infect. 1999;1:1265–1273
  47. Bottinger E, Factor V, Tsang M, Weatherbee J, Kopp J, Qian S, et al. The recombinant proregion of transforming growth factor beta1 (latency-associated peptide) inhibits active transforming growth factor beta1 in transgenic mice. Proc Natl Acad Sci U S A. 1996;93:5877–5882
  48. Nomura KTH, Kuboki K, Inokuchi T. Transforming growth factor-beta-1 latency-associated peptide and soluble betaglycan prevent a glucose-induced increase in fibronectin production in cultured human mesangial cells. Nephron. 2002;91:606–611
  49. Bornstein P. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol. 1995;130:503–506
  50. Stenina OI, Krukovets I, Wang K, Zhou Z, Forudi F, Penn MS, et al. Increased expression of thrombospondin-1 in vessel wall of diabetic Zucker rat. Circulation. 2003;107:3209–3215
  51. Wahab N, Schaefer L, Weston BS, Yiannikouris O, Wright A, Babelova A, et al. Glomerular expression of thrombospondin-1, transforming growth factor beta and connective tissue growth factor at different stages of diabetic nephropathy and their interdependent roles in mesangial response to diabetic stimuli. Diabetologia. 2005;48:2650–2660
  52. Raugi G, Lovett D. Thrombospondin secretion by cultured human glomerular mesangial cells. Am J Pathol. 1987;129:364–372
  53. Murphy-Ullrich JES-CS, Hook M. Transforming growth factor-beta complexes with thrombospondin. Mol Biol Cell. 1992;3:181–188
  54. Schultz-Cherry S, Chen H, Mosher DF, Misenheimer TM, Krutzsch HC, Roberts DD, et al. Regulation of transforming growth factor-beta activation by discrete sequences of thrombospondin 1. J Biol Chem. 1995;270:7304–7310
  55. Ribeiro S, Poczatek M, Schultz-Cherry S, Villain M, Murphy-Ullrich JE. The activation sequence of thrombospondin-1 interacts with the latency-associated peptide to regulate activation of latent transforming growth factor-beta. J Biol Chem. 1999;274:13586–13593
  56. Wang S, Skorczewski J, Feng X, Mei L, Murphy-Ullrich JE. Glucose up-regulates thrombospondin 1 gene transcription and transforming growth factor-{beta} activity through antagonism of cGMP-dependent protein kinase repression via upstream stimulatory factor 2. J Biol Chem. 2004;279:34311–34322
  57. Weber I, Harrison R, Iozzo R. Model structure of decorin and implications for collagen fibrillogenesis. J Biol Chem. 1996;271:31767–31770
  58. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-b by the proteoglycan decorin. Nature. 1990;346:281–284
  59. Hildebrand AR, Rasmussen M, Heinegard LM, Twardzik D, Border WA, Ruoslahti E. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J. 1994;302:527–534
  60. Mogyorosi A, Ziyadeh FN. Increased decorin mRNA in diabetic mouse kidney and in mesangial and tubular cells cultured in high glucose. Am J Physiol. 1998;275:F827–F832
  61. Holmes D, Wahab N, Mason R. Identification of glucose-regulated genes in human mesangial cells by mRNA differential display. Biochem Biophys Res Commun. 1997;238:179–184
  62. Murphy M, Godson C, Cannon S, Kato S, Mackenzie HS, Martin F, et al. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999;274:5830–5834
  63. Wahab N, Parker S, Sraer J-D, Mason R. The decorin high glucose response element and mechanism of its activation in human mesangial cells. J Am Soc Nephrol. 2000;11:1607–1619
  64. Schaefer L, Raslik I, Grone H-J, Schonherr E, Macakova K, Ugorcakova J, et al. Small proteoglycans in human diabetic nephropathy: discrepancy between glomerular expression and protein accumulation of decorin, biglycan, lumican, and fibromodulin. FASEB J. 2001;15:559–561
  65. Wolf G, Sharma K, Chen Y, Ericksen M, Ziyadeh FN. High glucose-induced proliferation in mesangial cells is reversed by autocrine TGF-b. Kidney Int. 1992;42:647–656
  66. Sharma K, Ziyadeh FN. The emerging role of transforming growth factor-b in kidney diseases. Am J Physiol. 1994;266:F829–F842
  67. Ziyadeh FN, Sharma K, Ericksen M, 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. 1994;93:536–542
  68. Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y, et al. Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes. 2003;52:2586–2593
  69. Usui H, Shikata K, Matsuda M, Okada S, Ogawa D, Yamashita T, et al. HMG-CoA reductase inhibitor ameliorates diabetic nephropathy by its pleiotropic effects in rats. Nephrol Dial Transplant. 2003;18:265–272
  70. Sassy-Prigent C, Heudes D, Mandet C, Belair MF, Michel O, Perdereau B, et al. Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes. 2000;49:466–475
  71. Pawluczyk I, Harris KP. Macrophages promote prosclerotic responses in cultured rat mesangial cells: a mechanism for the initiation of glomerulosclerosis. J Am Soc Nephrol. 1997;8:1525–1536
  72. Wang A, Hascall VC. Hyaluronan structures synthesized by rat mesangial cells in response to hyperglycemia induce monocyte adhesion. J Biol Chem. 2004;279:10279–10285
  73. van Berkel TJ OR, Hoekstra M, Kuiper J, Biessen E, van Eck M. Scavenger receptors: friend or foe in atherosclerosis?. Curr Opin Lipidol. 2005;16:525–535
  74. Nishida M, Fujinaka H, Matsusaka T, Price J, Kon V, Fogo AB, et al. Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis. J Clin Invest. 2002;110:1859–1868
  75. Oliver JA. Unexpected news in renal fibrosis. J Clin Invest. 2002;110:1763–1764
  76. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, et al. Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 1997;99:342–348
  77. Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerular capillary wall toward the center of disease: podocyte injury comes of age in diabetic nephropathy. Diabetes. 2005;54:1626–1634
  78. Steffes MW, Schmidt D, McCrery R, Basgen JM. Glomerular cell number in normal subjects and in type 1 diabetic patients. Kidney Int. 2001;59:2104–2113
  79. van Det N, Verhagen NA, Tamsma JT, Berden JH, Bruijn JA, Daha MR, et al. Diabetes (Regulation of glomerular epithelial cell production of fibronectin and transforming growth factor-beta by high glucose, not by angiotensin II). Diabetes. 1997;46:834–840
  80. De La Cruz MCI, Ziyadeh F, Isono M, Kouahou M, Han D, Kalluri R, et al. Effects of high glucose and TGF-B1 on the expression of collagen IV and vascular endothelial growth factor in mouse podocytes. Kidney Int. 2002;62:1–13
  81. Chen S, Kasama Y, Lee JS, Jim B, Marin M, Ziyadeh FN. Podocyte-derived vascular endothelial growth factor mediates the stimulation of alpha3(IV) collagen production by transforming growth factor-beta1 in mouse podocytes. Diabetes. 2004;53:2939–2949
  82. Chen S, Lee JS, Iglesias-de la Cruz MC, Wang A, Izquierdo-Lahuerta A, Gandhi NK, et al. Angiotensin II stimulates alpha3(IV) collagen production in mouse podocytes via TGF-β and VEGF signalling: implications for diabetic glomerulopathy. Nephrol Dial Transplant. 2005;20:1320–1328
  83. Benigni A, Zoja C, Corna D, Zatelli C, Conti S, Campana M, et al. Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol. 2003;14:1816–1824
  84. Ziyadeh F, Hoffman B, Han D, Iglesias-de la Cruz C, Hong S, Isono M, et al. Long-term prevention of renal insufficiency excess matrix gene expression and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-b antibody in db/db diabetic mice. Proc Natl Acad Sci U S A. 2000;97:8015–8020
  85. Chen S, Iglesias-de la Cruz M, Hong S, Isono M, Ziyadeh F. Reversibility of established diabetic glomerulopathy by anti-TGF-b antibodies in db/db mice. Biochem Biophys Res Commun. 2003;300:16–22
  86. Sharma K, Ziyadeh FN. Hyperglycemia and diabetic kidney disease (The case for transforming growth factor-beta as a key mediator). Diabetes. 1995;44:1139–1146
  87. Ziyadeh FN, Sharma K. Overview: combating diabetic nephropathy. J Am Soc Nephrol. 2003;14:1355–1357
  88. Del Prato S, Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2001;17:164–174

 Supported by the National Institutes of Health (R01DK053867-07, R01DK063017-04, U01DK076133-02 to K.S.), the American Diabetes Association, and the Juvenile Diabetes Research Foundation.

PII: S0270-9295(07)00009-5

doi: 10.1016/j.semnephrol.2007.01.008

Seminars in Nephrology
Volume 27, Issue 2 , Pages 153-160 , March 2007

Article Tools