NDT Advance Access originally published online on March 17, 2009
Nephrology Dialysis Transplantation 2009 24(8):2384-2391; doi:10.1093/ndt/gfp103
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Antifibrotic effects of pioglitazone on the kidney in a rat model of type 2 diabetes mellitus
1 Laboratory of Experimental Medicine, Hospital Alemán, Buenos Aires, Argentina 2 Urology Research Laboratory, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance 3 Department of Internal Medicine, The Charles Drew University 4 Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Correspondence and offprint requests to: Nestor F. Gonzalez-Cadavid; E-mail: ncadavid{at}ucla.edu
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Abstract |
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Background. Recent evidence suggests that treatment of type 2 diabetes with thiazolidinediones [peroxisome proliferator-activated receptor-
(PPAR-) agonists], ameliorates glomerulosclerosis and tubulointerstitial fibrosis in the rat kidney. In the current work, we have investigated whether these drugs, and specifically pioglitazone (PGT), act by preventing fibrosis and kidney dysfunction mainly through antioxidant and anti-inflammatory effects, independently of glycaemic control.
Methods. Male 2- to 3-month-old obese Zucker fa/fa (OZR) and ZDF fa/fa rats (ZDFR), and their control the lean Zucker rat (LZR), were used. Diabetic rats were given either a low dose (0.6 mg/kg/day) or a high dose (12 mg/ kg/day) of PGT in the chow for 2 or 4–5 months. Glycaemia, blood pressure, creatinine clearance and proteinuria were determined, and the underlying histopathology was defined with markers of fibrosis, glomerular damage, oxidative stress and inflammation by immunohistochemistry/ quantitative image analysis in tissue sections, and western blots and ad hoc assays in fresh tissue.
Results. PGT at low doses given for 4–5 months considerably reduced blood pressure, proteinuria and creatinine clearance. This was associated with amelioration of renal tissue damage and fibrosis, evidenced by the glomerulosclerosis, tubulointerstitial fibrosis, tubular atrophy and podocyte injury indexes, and of oxidative stress and inflammation, as shown by the decrease in the respective markers, although glycaemia remained high and obesity was not affected.
Conclusions. These results indicate that low doses of PGT ameliorate renal fibrosis and preserve renal function in this animal model of metabolic syndrome, independently of glycaemic control or effects on body weight.
Keywords: diabetic nephropathy; fibrosis; inflammation; oxidative stress; thiazolidinediones
Received for publication: 24.11.08
Accepted in revised form: 19. 2.09