氯沙坦对进展性肾炎模型大鼠肾小管-间质细胞低氧诱导因子及结缔组织生长因子的影响研究

目的:探讨氯沙坦对进展性肾炎模型大鼠肾小管-间质细胞低氧诱导因子-1α(HIF-1α)和结缔组织生长因子(CTGF)的影响及其肾保护作用机制。方法:将大鼠行右肾切除并注射鼠单克隆IgG(OX-7)抗Thy1.1抗体2次建立进展性肾炎大鼠模型,建模成功后取部分大鼠作为模型组,将剩余大鼠再分为对照组和氯沙坦高、低剂量组(80、20mg·kg-1·d-1);另取大鼠设立假手术组,每组5只,各组灌胃给予相应药物连续4周,观察各组大鼠24h尿蛋白、血肌酐、HIF-1α mRNA、CTGF mRNA水平及肾组织病理变化。结果:与假手术组比较,模型组血肌酐、24h尿蛋白和肾间质面积、HIF-1αmRNA、CTGF mRNA表达均明显增强(P<0.01或P<0.001);与模型组比较,氯沙坦高、低剂量组血肌酐、CTGF mRNA表达均明显降低(P<0.05或P<0.01),但在24h尿蛋白、肾间质面积比值、HIF-1αmRNA水平方面氯沙坦高剂量组均明显降低(P<0.01),低剂量组无明显变化。病理观察发现,模型组大鼠肾小管-间质炎症细胞浸润并出现纤维化,氯沙坦高、低剂量组肾小管-间质的损伤较对照组均有改善。结论:氯沙坦可能通过降低进展性肾炎模型大鼠HIF-1α mRNA和CTGF mRNA表达,减轻肾小管-间质纤维化而发挥肾脏保护作用。

Effects of Losartan on Tubulointerstitial Hypoxia Inducible Factors and Connective Tissue Growth Factors in Progressive Nephritis Model Rats

OBJECTIVE： To probe into the effects and mechanism of losartan on tubulointerstitial hypoxia inducible factor-1 （HIF-1α） and connective tissue growth factor （CTGF）in progressive nephritis model rats. METHODS： The rats underwent right ne- phrectomy and was injected with IgG（OX-7） mouse monoclonal anti-Thyl. 1 antibody twice to establish progressive nephritis model. Then some model rats were included in model group and other rats were divided into control group and losartan high-dose and low-dose groups （80, 20 mg.kg-1.d-1）, some rats were selected and included in sham operation group with 5 rats in each group. Above three groups were given relevant drugs for four weeks intragastricaUy. The levels of 24 h urine protein, serum creatinine, HIF-1α mRNA and CTGF mRNA and pathological changes of kidney were observed. RESULTS： Compared with sham operation group, serum creatinine, 24 h urine protein, renal interstitium area, HIF-1α mRNA and CTGF mRNA expression in model groups increased significantly （P（0.01 or P（0.001） ; compared with model group, serum creatinine and CTGF mRNA expression in losartan high-dose and low-dose groups decreased significantly （P（0.05 or P（0.01）, while 24 h urine protein, renal interstitium area and HIF-1α mRNA level in losartan high-dose group decreased significantly （P（0.01） and had no obvious change in losartan low-dose group. Pathological observation of model group showed that inflammatory cell infiltration and renal fibrosis. Tubulointerstitial injury was ameliorated in losartan high-dose and low-dose groups, compared with control group. CONCLUSIONS： Losartan may protect kidney by decreasing the expression of HIF-1α mRNA and CTGF mRNA and tubulointerstitial fibrosis in the progres- sive nenhritis model rats.