法舒地尔对盐敏感大鼠肾小球硬化症的肾脏保护作用

目的探讨Rho激酶通路是否参与高血压肾小球硬化症的发病机制，并评价法舒地尔对肾脏的保护作用。方法Dalai盐敏感（DS）大鼠21只和盐抵抗（DR）大鼠12只，均从6周龄开始喂以高盐饮食，形成肾衰竭模型。11周龄时，DS大鼠完全随机分为2组：DS．法舒地尔组9只，给予法舒地尔30mg／（kg·d）；DS组12只，给予等量的0．9％氯化钠溶液，均持续7周。之后进行如下测定：血清肌酐水平，血尿素氮，肌酐清降率，蛋白尿等。结果7周后，与DR组大鼠相比Ds组大鼠收缩压升高（111±8）mmHg（1mmHg=0．133kPa）比（104±6）mmHg，P〈0．05]，之后Ds组大鼠收缩压逐渐升高，13周左右达到最高（1494-12）mmHg。7周后，与DR组大鼠相比DS组大鼠。肾功能减退，‘肾组织形态异常，蛋白尿增加。与DS组大鼠相比，DS-法舒地尔组大鼠在没有改变血压水平的情况下肾功能改善：血清肌酐水平降低26％（3．9±0．4）g／／L比（5．4±0．6）∥L，P〈0．05]，血尿素氮降低41％（214±33）g／L比（364±41）g／L，P〈0．05]，肌酐清降率升高42％（2．08±0．33）ml／min比（1．46±0．47）ml／min，P〈0．05]，蛋白尿降低24％（17±3）mg／d比（22±1）mg／d，P〈0．05]；组织学检查：未治疗的DS大鼠组入球小动脉损伤分数（AIS）高于DR大鼠组（121±16）％比（9±1）％，P〈0．01]。未治疗的DS大鼠组被膜下近髓皮质肾小球损伤分数（GIS）高于DR大鼠组（92±13）％比（4±1）％，P〈0．01]。缓慢注入法舒地尔治疗组使这些变化得到改善，尤其在被膜下水平的肾小球损伤分数（48±3）％比（4±1）％，P〈0．05]。法舒地尔治疗也弱化了近髓皮质肾小球评分指数（63±8）％比（6±2）％，P〈0．05]。DR组与DS一法舒地尔组大鼠肾功能改善、蛋白尿、组织学检查比较，差异无统计学意义（P〉0．05）。结论DS大鼠Rho激酶通路可能独立于血压之外部分参与高血压。肾小球硬化症的发病机制。Rho激酶通路抑制剂可能用于高血压肾小球硬化症的肾脏保护方面的治疗。

Effect of fasudil on glomerulosclerosis in dahl salt-sensitive rats

Objective To explore whether the Rho-Rho-kinase pathway is involved in the process of hypertensive glomerulosclerosis and to assess the therapeutic effect of fasudil which is a specific Rho-kinase inhibitor. Methods Dahl salt-sensitive rats （DS） and Dahl salt-resistant rats （DR） were fed a high-salt diet. Fasudil 30 mg/（ kg · d） ] was administered for 7 weeks to DS starting. Results After 7 weeks, untreated DS had decreased kidney function, increased proteinuria and abnormal morphological findings. The systolic blood pressure ia 7-week-old DS rats was already higher than that in DR rats （ 111±8） mm Hg vs （ 104 ±6） mm Hg, P 〈0.05], and it gradually increased and reached a maximum after around 13 weeks vs （149 ± 12） mm Hg. Chronic fasudil treatment significantly improved renal function （serum creatinine, -26% （3.9 ＋0.4） g/L vs （5.4 ±0.6） g/L, P 〈 0.05 ], blood urea nitrogen （214 ±33 ） g/L vs （ 364 ± 41 ） g/L, P 〈 0.05 ], creatinine clearance （2.08 ±0.33 ） ml/min vs （ 1.46 ± 0.47） ml/min ] and proteinuria （ -24% ） （ 17 ＋ 3） mg/d vs （23 ＋ 1 ） mg/d ]. Long- term fasudil treatment significantly attenuated the symptoms （92 ± 13 ）% vs （4 ＋ 1 ）%, P 〈 0.01 ]. The suhcapsular symptoms and juxtamedullary cortex symptoms were markedly improved in untreated DS rats than those in DR rats. Long term fasudil treatment caused significant amelioration of these changes, especially in the glomeruli at subcapsular level （48 ± 3） % vs （4 ± 1 ） %, P 〈 0.05 ]. Fasudil treatment also attenuated the glomerular score index at the juxtamedullary cortex （ 63 ± 8 ） % vs （ 6±2 ） %, P 〈 0.05 ]. However, there were still significant differences in the blood pressure and aforementioned parameters between DR and fasudil-treated DS. Conclusions These results suggest that the Rho-Rho-kinase pathway may be partly responsible for the pathogenesis of hypertensive glomerulosclerosis in DS. Long term inhibition of the Rho-Rho-kinase pathway may be a new strategy for treating hypertensive nephrosclerosis.