PPAR-γ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-β
PPAR-γ agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-β
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DOI：
10.1038/labinvest.2008.104
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发表时间：
2009-01-01
影响因子：
5
通讯作者：
Yorioka, Noriaki
中科院分区：
文献类型：
--
作者：
Kawai, Toru;Masaki, Takao;Yorioka, Noriaki
噻唑烷二酮类（TZDs）是一种人工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形成中发挥重要作用。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，但确切机制尚不清楚。特别是，只有少数研究报道了TZD在非糖尿病肾小管间质纤维化和炎症模型中的肾保护作用。因此，我们研究了TZD曲格列酮在单侧输尿管梗阻（UUO）小鼠模型中的抗纤维化和抗炎作用。C57 BL/6 J小鼠经历UUO，并在3天和7天后进行研究。将动物分成三组，并通过管饲法接受对照媒介物、曲格列酮（150 mg/kg/天）或曲格列酮（300 mg/kg/天）。收获肾脏用于形态学、mRNA和蛋白质分析。逆转录酶-PCR用于评估转化生长因子-β 1（TGF-β 1）和TGF-β 1 I型受体（TGF β R-I）的表达。通过蛋白质印迹（TGF β R-I）和免疫染色（TGF β R-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，曲格列酮治疗组小鼠的α-SMA、I型胶原和F4/80的表达降低。曲格列酮处理的小鼠中PCNA阳性间质细胞的数量减少。与对照组相比，曲格列酮治疗组TGF-β 1 mRNA和TGF-β R-I mRNA及蛋白表达降低。曲格列酮治疗的有益作用也具有剂量依赖性。在UUO模型中，PPAR-gamma激动剂显著降低TGF-β并减轻肾间质纤维化和炎症。
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-beta 1 (TGF-beta 1) and the TGF-beta 1 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-beta 1 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.