血管紧张素Ⅱ受体拮抗剂对慢性肾衰竭大鼠肾小管上皮细胞增殖和转分化的影响

目的：探讨血管紧张素Ⅱ受体拮抗剂（ARB）losartan对慢性肾衰竭（CRF）大鼠肾小管上皮细胞增殖和转分化的影响。方法：Wistar大鼠随机分为假手术（Sham）组、模型（Nx）组、ARB小剂量（ARB15,losartan 15mg·kg^-1·d^-1灌胃）组、ARB大剂量（ARB150,losartan 150mg·kg^-1·d^-1灌胃）组。5/6肾切除制作CRF模型。12周后,观察各组肾功能、蛋白尿、肾重/体重（BW）、心脏重量/BW、肾脏病理变化,免疫组化观察肾脏胰岛素样生长因子-1（IGF-1）、α-平滑肌肌动蛋白（α-SMA）、Vimentin表达变化及增殖细胞核抗原（PCNA）阳性细胞数,TUNEL法观察细胞凋亡。结果：（1）Nx组大鼠Scr、BUN、24h尿蛋白定量、肾重/BW、心脏重量/BW均明显高于Sham组（P〈0.05）;ARB治疗后肾功能明显改善、蛋白尿减少、肾重/BW、心脏重量/BW降低（P〈0.05）。（2）Nx组大鼠肾组织有明显的肾小球硬化及肾小管间质损伤,肾小球硬化指数（GSI）及肾小管间质损伤指数（TII）均较Sham组明显增高;ARB治疗后GSI及TII均较Nx组降低（P〈0.05）。（3）与Sham组比较,Nx组肾间质IGF-1表达明显增加（P〈0.05）,ARB可明显减少IGF-1的表达（P〈0.05）。（4）Sham组肾组织可见α-SMA表达,肾间质无Vimentin表达;Nx组肾间质Vimentin及α-SMA表达增加（均P〈0.05）,ARB治疗后较Nx组两者表达减少（P〈0.05）。（5）Nx组TUNEL阳性细胞和PCNA阳性细胞均明显增加,ARB治疗对TUNEL阳性细胞无明显影响,但可明显减少PCNA阳性细胞数（P〈0.05）。结论：ARB可明显减轻CRF大鼠的肾损伤,该作用与抑制局部IGF-1表达和肾小管上皮细胞转分化以及改变细胞凋亡与增生的平衡有关。

Effect of AngiotensinⅡType-1 Receptor Blocker on Renal Tubulointerstitial Cell Transdifferentiation and Proliferation in 5/6 Nephrectomy Rats

Objective：To assess the effect of losartan, an angiotensin Ⅱ type - 1 receptor blocker （ARB）, on the renal tubulointerstitial cell transdifferentiation and proliferation in chronic renal failure （CRF） rats. Methods：Wistar rats were randomly divided into 4 groups： Sham operation group （sham）, nephrectomy group （Nx）, low - dose （ 15 mg·kg^-1·d^-1 ） ARB treated group （ARB15） and high-dose （150 mg·kg^-1·d^-1） ARB treated group （ARB150）. CRF was induced by 5/6 nephrectomy. Twelve weeks after operation, renal function, proteinuria, renal, heart and body weight were measured and renal pathology was observed. The expressions of insulin- like growth factor- 1 （IGF- 1）, alpha- smooth muscle actin （α- SMA）, Vimentin in tubulointerstitial were assessed by immunohistochemistry. Tubulointerstitial Cell Proliferation was assessed by measuring proliferating cell nuclear antigen （PCNA） and tubulointerstitial cell apoptosis was tested by terminal deoxynucleotidyl transferase （TdT） -mediated dUTP- biotin nick end labeling （TUNEL） essay. Results： （1） Compared with sham ones, Nx rats showed increased serum creatinine （Scr）, BUN, 24 - hour proteinuria, renal weight/body weight and heart weight/body weight （ P 〈 0.05 ）. ARB inhibited the increase of above index （ P 〈 0.05）. （2） Nx rats showed higher glomerular sclerosis index （GSI） and the tubulointerstitial index （TII） than the sham. ARB decreased GSI and TII （P〈0.05）. （3） IGF- 1 strongly expressed in renal interstitium in Nx rats, and was down - regulated by ARB. （4） Alpha - SMA was confined to vascular smooth muscle cell in sham rats, while strongly expressed within interstitium in Nx rats. ARB decreased the expression of α - SMA （ P 〈 0.05 ）. Vimentin strongly expressed in interstitium of Nx rats compared with sham rats and was down- regulated by ARB. Conclusion：ARB markedly ameliorates renal injury in CRF rats. The underlying mechanisms is, at least partly, rel