摘要
目的观察Rho/Rho激酶通路是否参与醛固酮加氯化钠诱导的肾脏损伤并探讨可能的机制。方法把单肾切除、进饮1%氯化钠的SD大鼠随机分为3组：对照组（2%乙醇皮下泵入）、醛固酮组（2%乙醇＋醛固酮0.75μg/h皮下泵入）和醛固酮＋法舒地尔（fasudil）组（2%乙醇＋醛固酮0.75μg/h皮下泵入＋fasudil 10 mg·kg^-1·d^-1皮下注射）。5周后,检测3组大鼠血压、尿蛋白改变;PAS染色和Masson三染法观察肾脏组织学变化;放射免疫方法检测肾皮质血管紧张素Ⅱ（AngⅡ）水平;Western印迹法检测血管紧张素转化酶（ACE）、磷酸化（p）RhoA及p-MYPT1水平;实时定量PCR检测转化生长因子β1（TGF-β1）及胶原Ⅰ、ⅢmRNA表达。结果与对照组比较,醛固酮诱发了严重的高血压[（193±3）mm Hg比（130±4）mm Hg,P〈0.05]、大量尿蛋白量（24 h）[（362±93）mg比（22±3）mg,P〈0.05]及肾小球、肾小管间质损伤,同时伴随肾皮质AngⅡ水平[（154±16）pmol/g比（81±8）pmol/g,P〈0.05]及ACE表达增高,RhoA及Rho激酶活性增强,肾皮质TGF-β1、胶原Ⅰ、胶原ⅢmRNA表达增加。而fasudil在抑制Rho激酶活性的同时,在没有影响血压的情况下,显著减少了尿蛋白量（24 h）[（96±22） mg],减轻了肾小球及肾小管间质损伤,并且减少了肾皮质TGF-β1、胶原Ⅰ、胶原ⅢmRNA表达。但肾内AngⅡ水平[（148±11）pmol/g]、ACE及RhoA表达无改变。结论Rho/Rho激酶通路参与了醛固酮加氯化钠诱导的肾损伤。fasudil对醛固酮加氯化钠肾脏损伤的保护作用并非通过抑制肾内ACE过表达及AngⅡ增多而实现。
Objective To investigate whether Rho/Rho kinase is involved in the pathogenesis of aldosterone/salt-induced renal injury. Methods Twenty-six uninephrectomized rats which were limited to drink only 1% sodium chloride were divided randomly into three groups： control [2% ethanol, subcutaneous （SC）], aldosterone （0.75μg/h aldosterone, SC） and aldosterone （0.75μg/h aldosterone, SC） plus fasudil（10 mg·kg^-1·d^-1, SC）. After treatment for 5 weeks, systolic blood pressure, proteinuria, renal histological examination, angiotensin Ⅱ level, expression of phospho-RhoA, phospho-MYPT1 （represent Rho kinase activity） and ACE by Western blot and mRNA expression of TGF-β1, collagen Ⅰ and collagen Ⅲ by real-time PCR were all tested. Results Aldosterone plus salt induced severe hypertension[（ 193±3 ） mm Hg vs. （130±4） mm Hg, P〈0.05], mass proteinuria[（362±93） mg/24 h vs. （22±3） mg/24 h, P〈0.05] and severe glomerular proliferative lesion and tubular interstitial fibrosis, accompanied by augmented angiotensin Ⅱ level [（154±16） pmol/g vs. （81±8） pmol/g, P〈0.05）] and increased expression of phospho-RhoA and phospho-MYPT1, as well as TGF-β1, collagen Ⅰ and collagen Ⅲ mRNA in the cortex. But fasudil, a kind of Rho-kinase inhibitor, significantly ameliorated the above effects without changes of angiotensin Ⅱ level, ACE and phospho-RhoA expression and systolic blood pressure. Conclusions Increased cortical Rho/Rho-kinase is involved in aldosterone-induced renal injury. The renoprotection of fasudil is not carried out via suppressing increased cortical angiotensin Ⅱ level and ACE overexpression.
出处
《中华肾脏病杂志》
CAS
CSCD
北大核心
2007年第12期800-805,共6页
Chinese Journal of Nephrology
作者简介
通讯作者：张锦，Email：zhangjininsy@gmail．com
