Kawai Toru, Masaki Takao, Doi Shigehiro, Arakawa Tetsuji, Yokoyama Yukio, Doi Toshiki, Kohno Nobuoki, Yorioka Noriaki
Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Lab Invest. 2009 Jan;89(1):47-58. doi: 10.1038/labinvest.2008.104. Epub 2008 Nov 10.
Thiazolidinediones (TZDs), synthetic peroxisome proliferator-activated receptor (PPAR)-gamma 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-beta1 (TGF-beta1) and the TGF-beta1 type I receptor (TGF beta R-I). Protein expression was assessed by western blotting (TGF beta R-I) and immunostaining (TGF beta R-I, alpha-smooth muscle actin (alpha-SMA), type I collagen (collagen I), F4/80, and proliferating cell nuclear antigen (PCNA)). The expression of alpha-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-beta1 mRNA and TGF beta R-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-gamma agonist significantly reduced TGF-beta and attenuated renal interstitial fibrosis and inflammation in the model of UUO.
噻唑烷二酮类药物（TZDs）是合成的过氧化物酶体增殖物激活受体（PPAR）-γ配体，在胰岛素增敏和脂肪生成中起核心作用。据报道，TZDs在糖尿病和非糖尿病肾病模型中均发挥保护作用，但其确切机制尚不清楚。特别是，仅有少数研究报道了TZDs在非糖尿病肾小管间质纤维化和炎症模型中的肾脏保护作用。因此，我们在单侧输尿管梗阻（UUO）小鼠模型中研究了TZDs曲格列酮的抗纤维化和抗炎作用。C57BL/6J小鼠接受UUO手术，并在术后3天和7天进行研究。动物分为三组，分别通过灌胃给予对照载体、曲格列酮（每天150 mg/kg）或曲格列酮（每天300 mg/kg）。采集肾脏进行形态学、mRNA和蛋白质分析。采用逆转录聚合酶链反应（RT-PCR）评估转化生长因子-β1（TGF-β1）和TGF-β1Ⅰ型受体（TGFβR-Ⅰ）的表达。通过蛋白质印迹法（TGFβR-Ⅰ）和免疫染色法（TGFβR-Ⅰ、α平滑肌肌动蛋白（α-SMA）、Ⅰ型胶原（胶原Ⅰ）、F4/80和增殖细胞核抗原（PCNA））评估蛋白质表达。与对照组相比，曲格列酮治疗的小鼠中α-SMA、胶原Ⅰ和F4/80的表达降低。曲格列酮治疗的小鼠中PCNA阳性间质细胞数量减少。与对照组相比，曲格列酮治疗组的TGF-β1 mRNA、TGFβR-Ⅰ mRNA和蛋白质表达降低。曲格列酮治疗的有益效果也呈剂量依赖性。PPAR-γ激动剂在UUO模型中显著降低TGF-β水平，减轻肾间质纤维化和炎症。
