Skip to main content
SpringerLink
Log in

PPAR-γ Ligands and Diabetic Nephropathy

  • Chapter
Book cover The Diabetic Kidney

Part of the book series: Contemporary Diabetes ((CDI))

  • 1330 Accesses

Abstract

Peroxisome proliferator-activated receptors (PPARs), originally cloned in an attempt to identify the molecular mediators of peroxisome proliferation in the liver of rodents, are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily (1,2). To date, three isoforms (PPAR-α, -β/δ, and -gg) have been cloned and characterized by their unique expression patterns, different ligand-binding specificity, and distinct metabolic functions (3). On ligand binding, PPARs form heterodimers with retinoid X receptor (RXR) proteins and bind to PPAR response elements within the promoter regions of target genes. A variety of natural and synthetic ligands for PPARs have been identified. As natural ligands for PPAR-α, some polyunsaturated fatty acids (FAs), oxidized phospholipids, and lipoprotein can activate PPAR-α (4). 15-Deoxy-δ-12, 14-prostaglandin J2 (15dPGJ2s) derived from prostaglandin D2 can activate PPAR-γ as a natural ligand (5). Among synthetic ligands, the hypolipidemic fibrate drugs such as fenofibrate and gemfibrozil bind to PPAR-α (6,7). Thiazolidinediones (TZDs) such as troglitazone, pioglitazone, and rosiglitazone, are well-known synthetic ligands for PPAR-γ (8). PPARs have been reported to regulate diverse cell functions, including FA metabolism, adipocyte differentiation, inflammation, atherosclerosis, and cell cycle (9–12). PPAR-α has an important role in lipid metabolism, especially in the liver (7).It is suggested that PPAR-β/δ carries out the effects in cell survival and carcinogenesis in the colon (13). PPAR-γ plays a pivotal role in adipogenesis and its activation by TZDs improves insulin sensitivity through adipocyte differentiation (14). TZDs have been

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 299.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Corton JC, Anderson SP, Stauber A. Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol 2000;40:491–518.

    Article  PubMed  CAS  Google Scholar 

  2. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 1990;347:645–650.

    Article  PubMed  CAS  Google Scholar 

  3. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal betaoxidation pathway by a novel family of nuclear hormone receptors. Cell 1992;68:879–887.

    Article  PubMed  CAS  Google Scholar 

  4. Ziouzenkova O, Perrey S, Asatryan L, et al. Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Proc Natl Acad Sci USA 2003;100:2730–2735.

    Article  PubMed  CAS  Google Scholar 

  5. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, Lehmann JM. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 1995;83:813–819.

    Article  PubMed  CAS  Google Scholar 

  6. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997;94:4312–4317.

    Article  PubMed  CAS  Google Scholar 

  7. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98:2088–2093.

    PubMed  CAS  Google Scholar 

  8. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995;270:12,953–12,956.

    Article  PubMed  CAS  Google Scholar 

  9. Guan Y, Breyer MD. Peroxisome proliferator-activated receptors (PPARs): novel therapeutic targets in renal disease. Kidney Int 2001;60:14–30.

    Article  PubMed  CAS  Google Scholar 

  10. Willson TM, Lambert MH, Kliewer SA. Peroxisome proliferator-activated receptor gamma and metabolic disease. Annu Rev Biochem 2001;70:341–367.

    Article  PubMed  CAS  Google Scholar 

  11. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 1999;20:649–688.

    Article  PubMed  CAS  Google Scholar 

  12. Fajas L, Debril MB, Auwerx J. Peroxisome proliferator-activated receptor-gamma: from adipogenesis to carcinogenesis. J Mol Endocrinol 2001;27:1–9.

    Article  PubMed  CAS  Google Scholar 

  13. Wu GD. A nuclear receptor to prevent colon cancer. N Engl J Med 2000;342:651–653.

    Article  PubMed  CAS  Google Scholar 

  14. Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia 1999;42:1033–1049.

    Article  PubMed  CAS  Google Scholar 

  15. Jones AB. Peroxisome proliferator-activated receptor (PPAR) modulators: diabetes and beyond. Med Res Rev 2001;21:540–552.

    Article  PubMed  CAS  Google Scholar 

  16. Fajas L, Fruchart JC, Auwerx J. PPARgamma3 mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett 1998;438:55–60.

    Article  PubMed  CAS  Google Scholar 

  17. Rosen ED, Spiegelman BM. PPARgamma: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 2001;276:37,731–37,734. Epub 2001 Jul 17.

    Article  PubMed  CAS  Google Scholar 

  18. Fajas L, Auboeuf D, Raspe E, et al. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem 1997;272:18,779–18,789.

    Article  PubMed  CAS  Google Scholar 

  19. Escher P, Wahli W. Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutat Res 2000;448:121–138.

    PubMed  CAS  Google Scholar 

  20. Juge-Aubry CE, Hammar E, Siegrist-Kaiser C, et al. Regulation of the transcriptional activity of the peroxisome proliferator-activated receptor alpha by phosphorylation of a ligand-independent transactivating domain. J Biol Chem 1999;274:10,505–10,510.

    Article  PubMed  CAS  Google Scholar 

  21. Shao D, Rangwala SM, Bailey ST, Krakow SL, Reginato MJ, Lazar MA. Interdomain communication regulating ligand binding by PPAR-gamma. Nature 1998;396:377–380.

    Article  PubMed  CAS  Google Scholar 

  22. Kliewer SA, Xu HE, Lambert MH, Willson TM. Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res 2001;56:239–263.

    Article  PubMed  CAS  Google Scholar 

  23. Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 1998;10:384–391.

    Article  PubMed  CAS  Google Scholar 

  24. Kliewer SA, Sundseth SS, Jones SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 1997;94:4318–4323.

    Article  PubMed  CAS  Google Scholar 

  25. Ellinghaus P, Wolfrum C, Assmann G, Spener F, Seedorf U. Phytanic acid activates the peroxisome proliferator-activated receptor alpha (PPARalpha) in sterol carrier protein 2-/ sterol carrier protein xdeficient mice. J Biol Chem 1999;274:2766–2772.

    Article  PubMed  CAS  Google Scholar 

  26. Moya-Camarena SY, Vanden Heuvel JP, Blanchard SG, Leesnitzer LA, Belury MA. Conjugated linoleic acid is a potent naturally occurring ligand and activator of PPARalpha. J Lipid Res 1999;40:1426–1433.

    PubMed  CAS  Google Scholar 

  27. Lin Q, Ruuska SE, Shaw NS, Dong D, Noy N. Ligand selectivity of the peroxisome proliferatoractivated receptor alpha. Biochemistry 1999;38:185–190.

    Article  PubMed  CAS  Google Scholar 

  28. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM. PPARgamma promotes monocyte/ macrophage differentiation and uptake of oxidized LDL. Cell 1998;93:241–252.

    Article  PubMed  CAS  Google Scholar 

  29. Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 1998;93:229–240.

    Article  PubMed  CAS  Google Scholar 

  30. Lambe KG, Tugwood JD. A human peroxisome-proliferator-activated receptor-gamma is activated by inducers of adipogenesis, including thiazolidinedione drugs. Eur J Biochem 1996;239:1–7.

    Article  PubMed  CAS  Google Scholar 

  31. Lowell BB. PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 1999;99:239–242.

    Article  PubMed  CAS  Google Scholar 

  32. Rosen ED, Sarraf P, Troy AE, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611–617.

    Article  PubMed  CAS  Google Scholar 

  33. Wu Z, Rosen ED, Brun R, et al. Cross-regulation of C/EBP alpha and PPAR gamma controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol Cell 1999;3:151–158.

    Article  PubMed  CAS  Google Scholar 

  34. Spiegelman BM, Hu E, Kim JB, Brun R. PPAR gamma and the control of adipogenesis. Biochimie 1997;79:111,112.

    Google Scholar 

  35. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12,14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995;83:803–812.

    Article  PubMed  CAS  Google Scholar 

  36. Xu HE, Lambert MH, Montana VG, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999;3:397–403.

    Article  PubMed  CAS  Google Scholar 

  37. Camp HS, Li O, Wise SC, et al. Differential activation of peroxisome proliferator-activated receptorgamma by troglitazone and rosiglitazone. Diabetes 2000;49:539–547.

    Article  PubMed  CAS  Google Scholar 

  38. Kubota N, Terauchi Y, Miki H, et al. PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell 1999;4:597–609.

    Article  PubMed  CAS  Google Scholar 

  39. Hara K, Okada T, Tobe K, et al. The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun 2000;271:212–216.

    Article  PubMed  CAS  Google Scholar 

  40. Kadowaki T. Insights into insulin resistance and type 2 diabetes from knockout mouse models. J Clin Invest 2000;106:459–465.

    PubMed  CAS  Google Scholar 

  41. Yamauchi T, Waki H, Kamon J, et al. Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes. J Clin Invest 2001;108:1001–1013.

    Article  PubMed  CAS  Google Scholar 

  42. Benson SC, Pershadsingh HA, Ho CI, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004;43:993–1002.

    Article  PubMed  CAS  Google Scholar 

  43. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation 2004;109:2054–2057.

    Article  PubMed  CAS  Google Scholar 

  44. Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W. Differential expression of peroxisome proliferatoractivated receptors (PPARs): tissue distribution of PPAR-alpha,-beta, and-gamma in the adult rat. Endocrinology 1996;137:354–366.

    Article  PubMed  CAS  Google Scholar 

  45. Su% JL, Simmons CJ, Wisely B, Ellis B, Winegar DA. Monitoring of PPAR alpha protein expression in human tissue by the use of PPAR alpha-specific MAbs. Hybridoma 1998;17:47–53.

    Article  PubMed  CAS  Google Scholar 

  46. Auboeuf D, Rieusset J, Fajas L, et al. Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 1997;46:1319–1327.

    Article  PubMed  CAS  Google Scholar 

  47. Mukherjee R, Jow L, Croston GE, Paterniti JR, Jr. Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARgamma2 versus PPARgamma1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 1997;272:8071–8076.

    Article  PubMed  CAS  Google Scholar 

  48. Guan Y, Zhang Y, Davis L, Breyer MD. Expression of peroxisome proliferator-activated receptors in urinary tract of rabbits and humans. Am J Physiol 1997;273:F1013–F1022.

    PubMed  CAS  Google Scholar 

  49. Kliewer SA, Forman BM, Blumberg B, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 1994;91:7355–7359.

    Article  PubMed  CAS  Google Scholar 

  50. Jain S, Pulikuri S, Zhu Y, et al. Differential expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and its coactivators steroid receptor coactivator-1 and PPAR-binding protein PBP in the brown fat, urinary bladder, colon, and breast of the mouse. Am J Pathol 1998;153:349–354.

    PubMed  CAS  Google Scholar 

  51. Yang T, Michele DE, Park J, et al. Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney. Am J Physiol 1999;277:F966–F973.

    PubMed  CAS  Google Scholar 

  52. Asano T, Wakisaka M, Yoshinari M, et al. Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) expresses in rat mesangial cells and PPARgamma agonists modulate its differentiation. Biochim Biophys Acta 2000;1497:148–154.

    Article  PubMed  CAS  Google Scholar 

  53. Iwashima Y, Eto M, Horiuchi S, Sano H. Advanced glycation end product-induced peroxisome proliferator-activated receptor gamma gene expression in the cultured mesangial cells. Biochem Biophys Res Commun 1999;264:441–448.

    Article  PubMed  CAS  Google Scholar 

  54. Sato K, Sugawara A, Kudo M, Uruno A, Ito S, Takeuchi K. Expression of peroxisome proliferatoractivated receptor isoform proteins in the rat kidney. Hypertens Res 2004;27:417–425.

    Article  PubMed  CAS  Google Scholar 

  55. Gorson DM. Significant weight gain with rezulin therapy. Arch Intern Med 1999;159:99.

    Google Scholar 

  56. Yoshimoto T, Naruse M, Nishikawa M, et al. Antihypertensive and vasculo-and renoprotective effects of pioglitazone in genetically obese diabetic rats. Am J Physiol 1997;272:E989–E996.

    PubMed  CAS  Google Scholar 

  57. The diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977–986.

    Article  Google Scholar 

  58. UK prospective diabetes study group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.

    Article  Google Scholar 

  59. Kumar S, Boulton AJ, Beck-Nielsen H, et al. Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia 1996;39:701–709.

    Article  PubMed  CAS  Google Scholar 

  60. Prigeon RL, Kahn SE, Porte D, Jr. Effect of troglitazone on B cell function, insulin sensitivity, and glycemic control in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 1998;83:819–823.

    Article  PubMed  CAS  Google Scholar 

  61. Fonseca VA, Valiquett TR, Huang SM, Ghazzi MN, Whitcomb RW. Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group. J Clin Endocrinol Metab 1998;83:3169–3176.

    Article  PubMed  CAS  Google Scholar 

  62. Spencer CM, Goa KL, Gillis JC. Tacrolimus. An update of its pharmacology and clinical efficacy in the management of organ transplantation. Drugs 1997;54:925–975.

    PubMed  CAS  Google Scholar 

  63. Imano E, Kanda T, Nakatani Y, et al. Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Care 1998;21:2135–2139.

    Article  PubMed  CAS  Google Scholar 

  64. McCarthy KJ, Routh RE, Shaw W, Walsh K, Welbourne TC, Johnson JH. Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion. Kidney Int 2000;58:2341–2350.

    Article  PubMed  CAS  Google Scholar 

  65. Buckingham RE, Al-Barazanji KA, Toseland CD, et al. Peroxisome proliferator-activated receptorgamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 1998;47:1326–1334.

    Article  PubMed  CAS  Google Scholar 

  66. Bakris GL. Protecting renal function in the hypertensive patient: Clinical guidelines. Am J Hypertens 2005;18:112–119.

    Article  Google Scholar 

  67. Ferrari P, Weidmann P. Insulin, insulin sensitivity and hypertension. J Hypertens 1990;8:491–500.

    Article  PubMed  CAS  Google Scholar 

  68. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–1607.

    Article  PubMed  CAS  Google Scholar 

  69. Kereiakes DJ, Willerson JT. Metabolic syndrome epidemic. Circulation 2003;108:1552,1553.

    Google Scholar 

  70. Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998;338:867–872.

    Article  PubMed  CAS  Google Scholar 

  71. Uchida A, Nakata T, Hatta T, et al. Reduction of insulin resistance attenuates the development of hypertension in sucrose-fed SHR. Life Sci 1997;61:455–464.

    Article  PubMed  CAS  Google Scholar 

  72. Grinsell JW, Lardinois CK, Swislocki A, et al. Pioglitazone attenuates basal and postprandial insulin concentrations and blood pressure in the spontaneously hypertensive rat. Am J Hypertens 2000;13:370–375.

    Article  PubMed  CAS  Google Scholar 

  73. Walker AB, Chattington PD, Buckingham RE, Williams G. The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. Diabetes 1999;48:1448–1453.

    Article  PubMed  CAS  Google Scholar 

  74. Sung BH, Izzo JL, Jr, Dandona P, Wilson MF. Vasodilatory effects of troglitazone improve blood pressure at rest and during mental stress in type 2 diabetes mellitus. Hypertension 1999;34:83–88.

    PubMed  CAS  Google Scholar 

  75. Guan Y. Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. J Am Soc Nephrol 2004;15:2801–2815.

    Article  PubMed  CAS  Google Scholar 

  76. Iijima K, Yoshizumi M, Ako J, et al. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in rat aortic smooth muscle cells. Biochem Biophys Res Commun 1998;247:353–356.

    Article  PubMed  CAS  Google Scholar 

  77. Law RE, Goetze S, Xi XP, et al. Expression and function of PPARgamma in rat and human vascular smooth muscle cells. Circulation 2000;101:1311–1318.

    PubMed  CAS  Google Scholar 

  78. Marx N, Schonbeck U, Lazar MA, Libby P, Plutzky J. Peroxisome proliferator-activated receptor gamma activators inhibit gene expression and migration in human vascular smooth muscle cells. Circ Res 1998;83:1097–1103.

    PubMed  CAS  Google Scholar 

  79. Zhang HY, Reddy SR, Kotchen TA. Antihypertensive effect of pioglitazone is not invariably associated with increased insulin sensitivity. Hypertension 1994;24:106–110.

    PubMed  Google Scholar 

  80. Zhang F, Sowers JR, Ram JL, Standley PR, Peuler JD. Effects of pioglitazone on calcium channels in vascular smooth muscle. Hypertension 1994;24:170–175.

    PubMed  CAS  Google Scholar 

  81. Fujiwara T, Ohsawa T, Takahashi S, et al. Troglitazone, a new antidiabetic agent possessing radical scavenging ability, improved decreased skin blood flow in diabetic rats. Life Sci 1998;6:2039–2047.

    Article  Google Scholar 

  82. Satoh H, Tsukamoto K, Hashimoto Y, et al. Thiazolidinediones suppress endothelin-1 secretion from bovine vascular endothelial cells: a new possible role of PPARgamma on vascular endothelial function. Biochem Biophys Res Commun 1999;254:757–763.

    Article  PubMed  CAS  Google Scholar 

  83. Sugawara A, Takeuchi K, Uruno A, et al. Transcriptional suppression of type 1 angiotensin II receptor gene expression by peroxisome proliferator-activated receptor-gamma in vascular smooth muscle cells. Endocrinology 2001;142:3125–3134.

    Article  PubMed  CAS  Google Scholar 

  84. Fujii M, Takemura R, Yamaguchi M, et al. Troglitazone (CS-045) ameliorates albuminuria in streptozotocin-induced diabetic rats. Metabolism 1997;46:981–983.

    Article  PubMed  CAS  Google Scholar 

  85. Isshiki K, Haneda M, Koya D, Maeda S, Sugimoto T, Kikkawa R. Thiazolidinedione compounds ameliorate glomerular dysfunction independent of their insulin-sensitizing action in diabetic rats. Diabetes 2000;49:1022–1032.

    Article  PubMed  CAS  Google Scholar 

  86. King GL, Ishii H, Koya D. Diabetic vascular dysfunctions: a model of excessive activation of protein kinase C. Kidney Int Suppl 1997;60:S77–S85.

    PubMed  CAS  Google Scholar 

  87. Derubertis FR, Craven PA. Activation of protein kinase C in glomerular cells in diabetes. Mechanisms and potential links to the pathogenesis of diabetic glomerulopathy. Diabetes 1994;43:1–8.

    Article  PubMed  CAS  Google Scholar 

  88. Greene DA, Lattimer SA, Sima AA. Sorbitol, phosphoinositides, and sodium-potassium-ATPase in the pathogenesis of diabetic complications. N Engl J Med 1987;316:599–606.

    Article  PubMed  CAS  Google Scholar 

  89. Williamson JR, Chang K, Frangos M, et al. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes 1993;42:801–813.

    Article  PubMed  CAS  Google Scholar 

  90. Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988;318:1315–1321.

    Article  PubMed  CAS  Google Scholar 

  91. Nishikawa T, Edelstein D, Du XL, et al. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000;404:787–790.

    Article  PubMed  CAS  Google Scholar 

  92. Sharma K, Ziyadeh FN. Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes 1995;44:1139–1346.

    Article  PubMed  CAS  Google Scholar 

  93. Koya D, Lee IK, Ishii H, Kanoh H, King GL. Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol. J Am Soc Nephrol 1997;8:426–435.

    PubMed  CAS  Google Scholar 

  94. Koya D, Jirousek MR, Lin YW, Ishii H, Kuboki K, King GL. 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.

    PubMed  CAS  Google Scholar 

  95. Kikkawa R, Haneda M, Uzu T, Koya D, Sugimoto T, Shigeta Y. Translocation of protein kinase C alpha and zeta in rat glomerular mesangial cells cultured under high glucose conditions. Diabetologia 1994;37:838–841.

    Article  PubMed  CAS  Google Scholar 

  96. 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. PPAR-ã Ligands and Diabetic Nephropathy 301

    Article  PubMed  CAS  Google Scholar 

  97. Lee IK, Koya D, Ishi H, Kanoh H, King GL. d-Alpha-tocopherol prevents the hyperglycemia induced activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway in vascular smooth muscle cell by an increase of DAG kinase activity.. 1999;45:183–190.

    PubMed  CAS  Google Scholar 

  98. Verrier E, Wang L, Wadham C, et al. PPARgamma agonists ameliorate endothelial cell activation via inhibition of diacylglycerol-protein kinase C signaling pathway: role of diacylglycerol kinase. Circ Res 2004;94:1515–1522.

    Article  PubMed  CAS  Google Scholar 

  99. Dandona P, Thusu K, Cook S, et al. Oxidative damage to DNA in diabetes mellitus. Lancet 1996;347:444,445.

    Article  Google Scholar 

  100. Leinonen J, Lehtimaki T, Toyokuni S, et al. New biomarker evidence of oxidative DNA damage in patients with non-insulin-dependent diabetes mellitus. FEBS Lett 1997;417:150–152.

    Article  PubMed  CAS  Google Scholar 

  101. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 1999;48:1–9.

    Article  PubMed  CAS  Google Scholar 

  102. Bursell SE, Clermont AC, Aiello LP, et al. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care 1999;22:1245–1251.

    Article  PubMed  CAS  Google Scholar 

  103. Davies GF, Khandelwal RL, Wu L, Juurlink BH, Roesler WJ. Inhibition of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by troglitazone: a peroxisome proliferator-activated receptorgamma (PPARgamma)-independent, antioxidant-related mechanism. Biochem Pharmacol 2001;62:1071–1079.

    Article  PubMed  CAS  Google Scholar 

  104. Inoue I, Katayama S, Takahashi K, et al. Troglitazone has a scavenging effect on reactive oxygen species. Biochem Biophys Res Commun 1997;235:113–116.

    Article  PubMed  CAS  Google Scholar 

  105. Fukui T, Noma T, Mizushige K, Aki Y, Kimura S, Abe Y. Dietary troglitazone decreases oxidative stress in early stage type II diabetic rats. Life Sci 2000;66:2043–2049. 106. Gumieniczek A. Effects of pioglitazone on hyperglycemia-induced alterations in antioxidative system in tissues of alloxan-treated diabetic animals. Exp Toxicol Pathol 2005;56:321-326.

    Article  PubMed  CAS  Google Scholar 

  106. Gumieniczek A. Effect of the new thiazolidinedione-pioglitazone on the development of oxidative stress in liver and kidney of diabetic rabbits. Life Sci 2003;74:553–562.

    Article  PubMed  CAS  Google Scholar 

  107. Dobrian AD, Schriver SD, Khraibi AA, Prewitt RL. Pioglitazone prevents hypertension and reduces oxidative stress in diet-induced obesity. Hypertension 2004;43:48–56.

    Article  PubMed  CAS  Google Scholar 

  108. Furuta T, Saito T, Ootaka T, et al. The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis 1993;21:480–485.

    PubMed  CAS  Google Scholar 

  109. Shikata K, Makino H. Role of macrophages in the pathogenesis of diabetic nephropathy. Contrib Nephrol 2001;134:46–54.

    PubMed  CAS  Google Scholar 

  110. Jiang C, Ting AT, Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391:82–86.

    Article  PubMed  CAS  Google Scholar 

  111. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptorgamma is a negative regulator of macrophage activation. Nature 1998;391:79–82.

    Article  PubMed  CAS  Google Scholar 

  112. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood 1996;87:2095–2147.

    PubMed  CAS  Google Scholar 

  113. Pfeilschifter J, Pignat W, Vosbeck K, Marki F. Interleukin 1 and tumor necrosis factor synergistically stimulate prostaglandin synthesis and phospholipase A2 release from rat renal mesangial cells. Biochem Biophys Res Commun 1989;159:385–394.

    Article  PubMed  CAS  Google Scholar 

  114. Pfeilschifter J, Rob P, Mulsch A, Fandrey J, Vosbeck K, Busse R. Interleukin 1 beta and tumour necrosis factor alpha induce a macrophage-type of nitric oxide synthase in rat renal mesangial cells. Eur J Biochem 1992;203:251–255.

    Article  PubMed  CAS  Google Scholar 

  115. Martin M, Neumann D, Hoff T, Resch K, DeWitt DL, Goppelt-Struebe M. Interleukin-1-induced cyclooxygenase 2 expression is suppressed by cyclosporin A in rat mesangial cells. Kidney Int 1994;45:150–158.

    Article  PubMed  CAS  Google Scholar 

  116. Rzymkiewicz D, Leingang K, Baird N, Morrison AR. Regulation of prostaglandin endoperoxide synthase gene expression in rat mesangial cells by interleukin-1 beta. Am J Physiol 1994;266:F39–F45.

    PubMed  CAS  Google Scholar 

  117. Colville-Nash PR, Gilroy DW. COX-2 and the cyclopentenone prostaglandins-a new chapter in the book of inflammation? Prostaglandins Other Lipid Mediat 2000;62:33–43.

    Article  PubMed  CAS  Google Scholar 

  118. Inoue H, Tanabe T, Umesono K. Feedback control of cyclooxygenase-2 expression through PPARgamma. J Biol Chem 2000;275:28,028–28,032.

    PubMed  CAS  Google Scholar 

  119. Chawla A, Barak Y, Nagy L, Liao D, Tontonoz P, Evans RM. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat Med 2001;7:48–52. 302 Isshiki et al.

    Article  PubMed  CAS  Google Scholar 

  120. Vaidya S, Somers EP, Wright SD, Detmers PA, Bansal VS. 15-Deoxy-Delta12,1412,14-prostaglandin J2 inhibits the beta2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor gamma ligation. J Immunol 1999;163:6187–6192.

    PubMed  CAS  Google Scholar 

  121. Petrova TV, Akama KT, Van Eldik LJ. Cyclopentenone prostaglandins suppress activation of microglia: down-regulation of inducible nitric-oxide synthase by 15-deoxy-Delta12,14-prostaglandin J2. Proc Natl Acad Sci USA 1999;96:4668–4673.

    Article  PubMed  CAS  Google Scholar 

  122. Straus DS, Pascual G, Li M, et al. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc Natl Acad Sci USA 2000;97:4844–4849.

    Article  PubMed  CAS  Google Scholar 

  123. Rossi A, Kapahi P, Natoli G, et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 2000;403:103–108.

    Article  PubMed  CAS  Google Scholar 

  124. Sawano H, Haneda M, Sugimoto T, Inoki K, Koya D, Kikkawa R. 15-Deoxy-Delta12,14-prostaglandin J2 inhibits IL-1beta-induced cyclooxygenase-2 expression in mesangial cells. Kidney Int 2002;61:1957–1967.

    Article  PubMed  CAS  Google Scholar 

  125. Ghosh SS, Gehr TW, Ghosh S, et al. PPARgamma ligand attenuates PDGF-induced mesangial cell proliferation: role of MAP kinase. Kidney Int 2003;64:52–62.

    Article  PubMed  CAS  Google Scholar 

  126. Yoshimura R, Matsuyama M, Segawa Y, et al. Study of peroxisome proliferator-activated receptor (PPAR)-gamma in renal ischemia-reperfusion injury. Transplant Proc 2004;36:1946–1948.

    Article  PubMed  CAS  Google Scholar 

  127. Sivarajah A, Chatterjee PK, Patel NS, et al. Agonists of peroxisome-proliferator activated receptorgamma reduce renal ischemia/reperfusion injury. Am J Nephrol 2003;23:267–276.

    Article  PubMed  CAS  Google Scholar 

  128. Naito Y, Takagi T, Uchiyama K, et al. Suppression of intestinal ischemia-reperfusion injury by a specific peroxisome proliferator-activated receptor-gamma ligand, pioglitazone, in rats. Redox Rep 2002;7:294–299.

    Article  PubMed  CAS  Google Scholar 

  129. Crook ED. The role of hypertension, obesity, and diabetes in causing renal vascular disease. Am J Med Sci 1999;317:183–188.

    Article  PubMed  CAS  Google Scholar 

  130. van Jaarsveld BC, Krijnen P, Pieterman H, et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group. N Engl J Med 2000;342:1007–1014.

    Article  PubMed  Google Scholar 

  131. Sawamura T, Kume N, Aoyama T, et al. An endothelial receptor for oxidized low-density lipoprotein. Nature 1997;386:73–77.

    Article  PubMed  CAS  Google Scholar 

  132. Chinetti G, Griglio S, Antonucci M, et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 1998;273:25,573–25,580.

    Article  PubMed  CAS  Google Scholar 

  133. Law RE, Meehan WP, Xi XP, et al. Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia. J Clin Invest 1996;98:1897–1905.

    Article  PubMed  CAS  Google Scholar 

  134. Murakami K, Tobe K, Ide T, et al. A novel insulin sensitizer acts as a coligand for peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and PPAR-gamma: effect of PPAR-alpha activation on abnormal lipid metabolism in liver of Zucker fatty rats. Diabetes 1998;47:1841–1847.

    Article  PubMed  CAS  Google Scholar 

  135. Arici M, Chana R, Lewington A, Brown J, Brunskill NJ. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma. J Am Soc Nephrol 2003;14:17–27.

    Article  PubMed  CAS  Google Scholar 

  136. Zafiriou S, Stanners SR, Polhill TS, Poronnik P, Pollock CA. Pioglitazone increases renal tubular cell albumin uptake but limits proinflammatory and fibrotic responses. Kidney Int 2004;65:1647–1653.

    Article  PubMed  CAS  Google Scholar 

  137. Ma LJ, Marcantoni C, Linton MF, Fazio S, Fogo AB. Peroxisome proliferator-activated receptorgamma agonist troglitazone protects against nondiabetic glomerulosclerosis in rats. Kidney Int 2001;59:1899–1910.

    Article  PubMed  CAS  Google Scholar 

  138. Guo B, Koya D, Isono M, Sugimoto T, Kashiwagi A, Haneda M. Peroxisome proliferator-activated receptor-gamma ligands inhibit TGF-beta 1-induced fibronectin expression in glomerular mesangial cells. Diabetes 2004;53:200–208.

    Article  PubMed  CAS  Google Scholar 

  139. Portilla D. Energy metabolism and cytotoxicity. Semin Nephrol 2003;23:432–438.

    Article  PubMed  CAS  Google Scholar 

  140. Ouali F, Djouadi F, Merlet-Benichou C, Bastin J. Dietary lipids regulate beta-oxidation enzyme gene expression in the developing rat kidney. Am J Physiol 1998;275:F777–F784.

    PubMed  CAS  Google Scholar 

  141. Fried LF, Orchard TJ, Kasiske BL. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001;59:260–269.

    Article  PubMed  CAS  Google Scholar 

  142. Smulders YM, van Eeden AE, Stehouwer CD, Weijers RN, Slaats EH, Silberbusch J. Can reduction in hypertriglyceridaemia slow progression of microalbuminuria in patients with non-insulin-dependent diabetes mellitus? Eur J Clin Invest 1997;27:997–1002.

    Article  PubMed  CAS  Google Scholar 

  143. Park CW, Zhang Y, Fan XF, et al. A PPAR alpha agonist improves diabetic nephropathy in db/db mice. J Am Soc Nephrol 2003;14:393A.

    Google Scholar 

  144. Wilmer WA, Dixon CL, Hebert C, Lu L, Rovin BH. PPAR-alpha ligands inhibit H2O2-mediatedactivation of transforming growth factor-beta1 in human mesangial cells. Antioxid Redox Signal 2002;4:877–884.

    Article  PubMed  CAS  Google Scholar 

  145. Hao CM, Redha R, Morrow J, Guan YF, Bailey MD. Hypertonic stress induces COX2 dependent prostacyclin synthesis in renal medullary interstitial cells (RMICs) and down-stream activation of PPAR delta dependent survival mechanism. J Am Soc Nephrol 2001;12:49A. 304

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan

    Keiji Isshiki MD, PhD

  2. Department of Endocrinology and Metabolism, Kanazawa Medical University, Uchinada, Kahoku, Ishikawa, Japan

    Daisuke Koya MD, PhD

  3. Second Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japan

    Masakazu Haneda MD, PhD

Authors
  1. Keiji Isshiki MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daisuke Koya MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masakazu Haneda MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Nephrology and Hypertension, Department of Medicine, Henry Ford Hospital, Detroit, MI

    Pedro Cortes MD

  2. Department of Internal Medicine M (Diabetes and Endocrinology), Aarhus University Hospital, Aarhus, Denmark

    Carl Erik Mogensen MD

Rights and permissions

Reprints and permissions

Copyright information

© 2006 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Isshiki, K., Koya, D., Haneda, M. (2006). PPAR-γ Ligands and Diabetic Nephropathy. In: Cortes, P., Mogensen, C.E. (eds) The Diabetic Kidney. Contemporary Diabetes. Humana Press. https://doi.org/10.1007/978-1-59745-153-6_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-59745-153-6_16

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-624-5

  • Online ISBN: 978-1-59745-153-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation