Chen Yumin, Luo Qiong, Xiong Zibo, Liang Wei, Chen Li, Xiong Zuying
Shenzhen Hospital, Health Science Center, Peking University, Shenzhen, PR China.
Int J Clin Exp Pathol. 2012;5(6):522-9. Epub 2012 Jul 17.
Chronic renal failure (CRF) mainly results from kidney fibrosis. Epithelial-to-mesenchymal transition (EMT) occurs in stressed tubular epithelial cells and contributes to renal fibrosis. Transforming growth factor-β1 (TGF-β1) has been shown to initiate and complete the whole EMT process. Peroxisome proliferators-activated receptor-γ (PPAR-γ) exerts anti-inflammatory, anti-fibrotic and vaculo-protective effects on different renal diseases. Telmisartan is a member of angiotensin II (Ang II) receptor blocker (ARB) family. Recent studies show that Telmisartan has a partial agonistic effect on PPAR-γ. Therefore, we tested the hypothesis that Telmisartan reverses the progression of induced EMT by TGF-β1 in cultured human renal proximal tubular epithelial (HK-2) cells. Cultured HK-2 cells were treated with TGF-β1 (3 ng/ml), a combination of TGF-β1 and Telmisartan (10-200 umol/L) and a combination of TGF-β1, Telmisartan and GW9662, a PPAR-γ antagonist for 48 hours. EMT was determined by quantitative real-time PCR analysis of E-cadherin (E-cad), Connective Tissue Growth Factor (CTGF) and PPAR-γ transcript expression and immunocytochemical analysis of E-cad, α-Smooth Muscle Actin (α-SMA) and PPAR-γ protein expression. TGF-β1 induced phenotypic EMT in cultured HK-2 cell line via significantly reduced E-cad expression and significantly increased CTGF, α-SMA expression in association with the loss of epithelial morphology. Telmisartan reversed all EMT markers in a dose-dependent manner which was inhibited by PPAR antagonist GW9662. In the present study, it was suggested that Telmisartan attenuated TGF-β1 induced EMT by agonistic activation of PPAR-γ.
慢性肾衰竭（CRF）主要由肾纤维化引起。上皮-间质转化（EMT）发生于应激的肾小管上皮细胞，并促进肾纤维化。已表明转化生长因子-β1（TGF-β1）启动并完成整个EMT过程。过氧化物酶体增殖物激活受体-γ（PPAR-γ）对不同的肾脏疾病发挥抗炎、抗纤维化和血管保护作用。替米沙坦是血管紧张素II（Ang II）受体阻滞剂（ARB）家族的一员。最近的研究表明，替米沙坦对PPAR-γ具有部分激动作用。因此，我们检验了以下假设：替米沙坦可逆转TGF-β1在培养的人肾近端小管上皮（HK-2）细胞中诱导的EMT进程。将培养的HK-2细胞用TGF-β1（3 ng/ml）、TGF-β1与替米沙坦（10 - 200 μmol/L）的组合以及TGF-β1、替米沙坦与PPAR-γ拮抗剂GW9662的组合处理48小时。通过对E-钙黏蛋白（E-cad）、结缔组织生长因子（CTGF）和PPAR-γ转录本表达进行定量实时PCR分析以及对E-cad、α-平滑肌肌动蛋白（α-SMA）和PPAR-γ蛋白表达进行免疫细胞化学分析来确定EMT。TGF-β1通过显著降低E-cad表达以及显著增加CTGF、α-SMA表达并伴有上皮形态丧失，在培养的HK-2细胞系中诱导表型EMT。替米沙坦以剂量依赖性方式逆转了所有EMT标志物，而这被PPAR拮抗剂GW9662所抑制。在本研究中，提示替米沙坦通过PPAR-γ的激动性激活减轻TGF-β1诱导的EMT。
