Hu Haiyan, Chen Wei, Ding Jiarong, Jia Meng, Yin Jingjing, Guo Zhiyong
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
Department of Nephrology, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
Exp Mol Pathol. 2015 Apr;98(2):277-85. doi: 10.1016/j.yexmp.2015.02.006. Epub 2015 Feb 16.
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 α-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).
肾结石是一种常见的肾脏疾病，也是慢性肾功能不全的主要原因之一。我们开发并利用乙醛酸诱导的小鼠草酸钙晶体沉积模型，来研究Rho相关蛋白激酶（ROCK）特异性抑制剂法舒地尔对草酸钙结晶和沉积所导致的肾损伤和纤维化的药理作用。连续五天给C57BL/6J小鼠腹腔注射乙醛酸，以建立小鼠草酸钙晶体形成和沉积模型。结果显示，与对照小鼠相比，乙醛酸诱导的模型小鼠肾组织中E-cad和Pan-ck的蛋白表达水平较低，而α-SMA和Vim的蛋白表达水平较高。在乙醛酸给药前用法舒地尔预处理动物后，蛋白表达的变化减弱。肾组织中ROCK、PAI-1和p-Smad蛋白的表达在乙醛酸处理后增加，而在动物用 法舒地尔预处理后增加程度减轻。乙醛酸给药后，肾组织中Smad2和Smad3的表达保持不变。乙醛酸诱导的草酸钙晶体形成和沉积会增强肾皮质和髓质中的细胞凋亡和增殖，而法舒地尔预处理能够减弱这种增强作用。结果表明，法舒地尔可减少乙醛酸诱导的肾钙晶体形成和沉积，并减缓钙晶体沉积引起的肾纤维化。其可能的机制可能与对Rho/ROCK信号转导和上皮-间质转化（EMT）的调节作用有关。
