NDT Advance Access originally published online on April 3, 2008
Nephrology Dialysis Transplantation 2008 23(9):2750-2760; doi:10.1093/ndt/gfn157
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Pioglitazone attenuates diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats
1 Department of Internal Medicine, Korea University, Ansan City 2 Department of Internal Medicine, Inje University, Goyang City, Kyungki-Do 3 Department of Internal Medicine, Korea University, Seoul 4 Department of Pathology, Inha University, Incheon, Korea
Correspondence and offprint requests to: Dae Ryong Cha, Department of Internal Medicine, Korea University Ansan-Hospital, 516 Kojan-Dong, Ansan City, Kyungki-Do, 425-020, Korea. Tel: +82-31-412-6590; Fax: +82-31-412-5574; E-mail: cdragn{at}unitel.co.kr
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Abstract |
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Background. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that play a role in insulin sensitivity, lipid metabolism and inflammation. However, the effects of PPAR
agonist on renal inflammation have not been fully examined in type 2 diabetic nephropathy.
Methods. In the present study, we investigated the effect and molecular mechanism of the PPAR agonist, pioglitazone, on the progression of diabetic nephropathy in type 2 diabetic rats. Inflammatory markers including NF-
B, MCP-1 and pro-fibrotic cytokines were determined by RT-PCR, western blot, immunohistochemical staining and EMSA. In addition, to evaluate the direct anti-inflammatory effect of PPAR agonist, we performed an in vitro study using mesangial cells.
Results. Treatment of OLETF rats with pioglitazone improved insulin sensitivity and kidney/body weight, but had a little effect on blood pressure. Pioglitazone treatment markedly reduced urinary albumin and MCP-1 excretion, and ameliorated glomerulosclerosis. In cDNA microarray analysis using renal cortical tissues, several inflammatory and profibrotic genes were significantly down-regulated by pioglitazone including NF-B, CCL2, TGFβ1, PAI-1 and VEGF. In renal tissues, pioglitazone treatment significantly reduced macrophage infiltration and NF-B activation in association with a decrease in type IV collagen, PAI-1, and TGFβ1 expression. In cultured mesangial cells, pioglitazone-activated endogenous PPAR transcriptional activity and abolished high glucose-induced collagen production. In addition, pioglitazone treatment also markedly suppressed high glucose-induced MCP-1 synthesis and NF-B activation.
Conclusions. These data suggest that pioglitazone not only improves insulin resistance, glycaemic control and lipid profile, but also ameliorates renal injury through an anti-inflammatory mechanism in type 2 diabetic rats.
Keywords: diabetic nephropathy; inflammation; nuclear factor-kappa B; PPAR agonist; type 2 diabetes
Received for publication: 13. 9.07
Accepted in revised form: 28. 2.08
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