1. ¹Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
2. ²Department of Advanced Nephrology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan

Correspondence: Dr T Masaki, MD, Department of Advanced Nephrology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City 734-8551, Japan. E-mail: masaki@hiroshima-u.ac.jp

Received 22 April 2008; Revised 18 September 2008; Accepted 19 September 2008; Published online 10 November 2008.

Abstract

Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)- ligands, have a central role in insulin sensitization and adipogenesis. It has been reported that TZDs exert protective effects in both diabetic and nondiabetic models of renal disease, although the exact mechanism is not well understood. In particular, only a few studies have reported the renoprotective effects of TZDs in nondiabetic models of tubulointerstitial fibrosis and inflammation. Therefore, we investigated the anti-fibrotic and anti-inflammatory effects of the TZD troglitazone in the mouse model of unilateral ureteral obstruction (UUO). C57BL/6J mice underwent UUO and were studied after 3 and 7 days. Animals were divided into three groups and received control vehicle, troglitazone (150 mg/kg per day) or troglitazone (300 mg/kg per day) by gavage. Kidneys were harvested for morphological, mRNA and protein analysis. Reverse-transcriptase–PCR was used to assess the expression of transforming growth factor-1 (TGF-1) and the TGF-1 type I receptor (TGFR-I). Protein expression was assessed by western blotting (TGFR-I) and immunostaining (TGFR-I, -smooth muscle actin (-SMA), type I collagen (collagen I), F4/80, and proliferating cell nuclear antigen (PCNA)). The expression of -SMA, collagen I, and F4/80 was decreased in mice treated with troglitazone compared with the control group. The numbers of PCNA-positive interstitial cells were decreased in mice treated with troglitazone. TGF-1 mRNA and TGFR-I mRNA and protein expression were decreased in the group treated with troglitazone compared with the control group. The beneficial effects of troglitazone treatment were also dose dependent. PPAR- agonist significantly reduced TGF- and attenuated renal interstitial fibrosis and inflammation in the model of UUO.