Fasudil prevents calcium oxalate crystal deposit and renal fibrogenesis in glyoxylate-induced nephrolithic mice
Fasudil prevents calcium oxalate crystal deposit and renal fibrogenesis in glyoxylate-induced nephrolithic mice
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法舒地尔可预防乙醛酸诱导的肾石小鼠的草酸钙晶体沉积和肾纤维化
DOI：
10.1016/j.yexmp.2015.02.006
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发表时间：
2015-04-01
影响因子：
3.6
通讯作者：
Guo, Zhiyong
中科院分区：
文献类型：
--
作者：
Hu, Haiyan;Chen, Wei;Guo, Zhiyong
肾结石是一种常见的肾脏疾病，是慢性肾功能不全的主要原因之一。我们建立了乙醛酸诱导的小鼠肾脏草酸钙结晶沉积模型，并利用该模型研究了Rho相关蛋白激酶（ROCK）特异性抑制剂法舒地尔（fasudil）对草酸钙结晶和沉积引起的肾损伤和纤维化的药理作用。采用乙醛酸连续5 d腹腔注射C57 BL/6 J小鼠，建立小鼠肾脏草酸钙结晶形成和沉积模型。结果显示，乙醛酸诱导模型小鼠肾组织中E-cad和Pan-ck蛋白表达水平较对照组降低，α-SMA和Vim蛋白表达水平较对照组升高。当动物在乙醛酸给药前用法舒地尔预处理时，蛋白质表达的变化减弱。ROCK、派-1和p-Smad蛋白在肾组织中的表达在乙醛酸处理后增加，当动物用法舒地尔预处理时，这种增加得到缓解。在乙醛酸给药后，肾组织中Smad 2和Smad 3的表达保持不变。乙醛酸可诱导肾皮质和髓质细胞凋亡和增殖，法舒地尔预处理可抑制乙醛酸诱导的肾组织钙结晶的形成和沉积，并可减缓钙结晶沉积引起的肾纤维化。其机制可能与调节Rho/ROCK信号转导和上皮-间质转化（EMT）有关。(C)© 2015 Elsevier Inc版权所有。
Nephrolithiasis is a common kidney disease and one of the major causes of chronic renal insufficiency. We develop and utilize a glyoxylate induced mouse model of kidney calcium oxalate crystal deposition for studying the pharmacological effects of fasudil, a Rho associated protein kinase (ROCK) specific inhibitor, on the kidney injury and fibrosis caused by calcium oxalate crystallization and deposition. Glyoxylate was administrated intraperitoneally to C57BL/6J mice for five consecutive days to establish a mouse model of kidney calcium oxalate crystal formation and deposition. The results showed that the protein expression levels of E-cad and Pan-ck were lower, and the protein expression levels of alpha-SMA and Vim were higher, in the kidney tissue of the glyoxylate induced model mice compared with the control mice. The changes in protein expression were weakened when the animals were pretreated with fasudil before glyoxylate administration. Expression of ROCK, PAI-1, and p-Smad proteins in the kidney tissue increased in response to glyoxylate treatment, and the increase was eased when the animals were pretreated with fasudil. Expression of Smad2 and Smad3 in the kidney tissue remained unchanged after glyoxylate administration. Cell apoptosis and proliferation in the kidney cortex and medulla were enhanced in response to the glyoxylate induced calcium oxalate crystal formation and deposition, and fasudil pre-treatment was able to attenuate the enhancement The results suggest that Fasudil reduces the glyoxylate induced kidney calcium crystal formation and deposition and slows down the kidney fibrogenesis caused by calcium crystal deposition. The possible mechanism may be related the regulatory effects on Rho/ROCK signal transduction and epithelial-mesenchymal transition (EMT). (C) 2015 Elsevier Inc All rights reserved.