The antifibrotic effect of a serine protease inhibitor in the kidney
The antifibrotic effect of a serine protease inhibitor in the kidney
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DOI：
10.1152/ajprenal.00586.2012
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发表时间：
2013-07-01
影响因子：
4.2
通讯作者：
Kitamura, Kenichiro
中科院分区：
文献类型：
--
作者：
Morinaga, Jun;Kakizoe, Yutaka;Kitamura, Kenichiro
间质纤维化是慢性肾脏疾病发展的最终共同途径。活化的成纤维细胞在肾纤维化的进展中具有极其重要的作用，而转化生长因子(TGF)- β(1)是成纤维细胞的主要激活因子。由于先前的报道表明丝氨酸蛋白酶抑制剂在体外有抑制tgf - β(1)信号的潜力，我们假设合成丝氨酸蛋白酶抑制剂甲磺酸卡莫他（CM）可以减缓肾纤维化的进展。tgf - β(1)显著提高肾成纤维细胞（NRK-49F细胞）中tgf - β I型受体ERK 1/2、Smad2/3磷酸化水平及α -平滑肌肌动蛋白（α - sma）、结缔组织生长因子（CTGF）、纤溶酶原激活物抑制剂-1等促纤维化标志物水平，CM均显著降低。在方案1中，8周龄雄性Sprague-Dawley大鼠进行单侧输尿管梗阻（UUO）治疗，同时给予CM缓释颗粒或载药治疗14天。方案2与方案1相似，只是在UUO后7天给予CM。通过天狼星红染色、胶原表达和羟脯氨酸水平测定，CM可显著改善肾纤维化。UUO显著提高了ERK1/2和Smad2/3的磷酸化水平以及α - sma、CTGF、前基质金属蛋白酶-2和基质金属蛋白酶-2的水平，而CM则显著降低了这些水平。CM的这些抗纤维化作用也在方案2中观察到。我们目前的研究结果表明，CM可能代表了一种通过抑制tgf - β(1)信号传导来治疗肾纤维化的新型治疗药物。
Interstitial fibrosis is a final common pathway for the progression of chronic kidney diseases. Activated fibroblasts have an extremely important role in the progression of renal fibrosis, and transforming growth factor (TGF)-beta(1) is a major activator of fibroblasts. Since previous reports have indicated that serine protease inhibitors have a potential to inhibit TGF-beta(1) signaling in vitro, we hypothesized that a synthetic serine protease inhibitor, camostat mesilate (CM), could slow the progression of renal fibrosis. TGF-beta(1) markedly increased the phosphorylation of TGF-beta type I receptor, ERK 1/2, and Smad2/3 and the levels of profibrotic markers, such as alpha-smooth muscle actin (alpha-SMA), connective tissue growth factor (CTGF), and plasminogen activator inhibitor-1, in renal fibroblasts (NRK-49F cells), and they were all significantly reduced by CM. In protocol 1, 8-wk-old male Sprague-Dawley rats were subjected to unilateral ureteral obstruction (UUO) and were concurrently treated with a slow-release pellet of CM or vehicle for 14 days. Protocol 2 was similar to protocol 1 except that CM was administered 7 days after UUO. CM substantially improved renal fibrosis as determined by sirius red staining, collagen expression, and hydroxyproline levels. The phosphorylation of ERK1/2 and Smad2/3 and the levels of alpha-SMA, CTGF, promatrix metalloproteinase-2, and matrix metalloproteinase-2 were substantially increased by UUO, and they were all significantly attenuated by CM. These antifibrotic effects of CM were also observed in protocol 2. Our present results suggest the possibility that CM might represent a new class of therapeutic drugs for the treatment of renal fibrosis through the suppression of TGF-beta(1) signaling.