全反式维甲酸对5/6肾大部切除大鼠肾间质纤维化的影响及其作用机制

 目的  探讨全反式维甲酸 (all-trans retinoic acid,atRA)对5/6肾大部切除 (5/6 nephrectomy,5/6Nx) 大鼠肾小管间质纤维化的作用及其机制。方法  成年雄性SD 大鼠行5/6Nx后2周分为3组:5/6Nx组 (大豆油1 mL·kg-1·d-1,n=11)、 atRA1 组 (atRA 5 mg·kg-1·d-1,n=10)、atRA2组 (atRA 10 mg·kg-1·d-1,n=11),另设Sham组即假手术组 (大豆油1 mL·kg-1·d-1,n=7)。经灌胃给药,每日1次,连续给药12 周。测定24 h尿蛋白量和血肌酐浓度;肾脏病理切片采用VG染色,对肾小管间质纤维化进行评分;用Western blot检测肾皮质中α平滑肌肌动蛋白 (α-smooth muscle actin,α-SMA)和纤溶酶原激活物抑制剂1 (plasminogen activator inhibitor-1,PAI-1)的蛋白表达。结果  术后14 周,atRA显著降低5/6Nx大鼠的24 h尿蛋白量和血肌酐浓度 (P均<0.05)。atRA显著降低该模型的肾小管间质纤维化 (P<0.01)。atRA显著下调该模型的肾皮质α-SMA和PAI-1表达 (P均<0.05),肾小管间质纤维化评分与α-SMA和PAI-1表达均呈显著正相关 (r分别为0.717 6和0.809 8,P均<0.01)。结论  atRA可减少5/6Nx大鼠的尿蛋白水平,抑制肾皮质α-SMA和PAI-1的蛋白表达,从而减轻肾间质纤维化。

Effect of all-trans retinoic acid on renal tubulointerstitial fibrosis in the rats with 5/6 nephrectomy and its mechanisms

ObjectiveTo investigate the effect of all-trans retinoic acid (atRA) on renal tubulointerstitial fibrosis in the rats with 5/6 nephrectomy and the involved mechanisms.Methods  Adult male SD rats underwent 5/6 nephrectomy (5/6Nx).Two weeks later,nephrectomized rats were divided into 3 groups:5/6Nx group (soybean oil of 1 mL·kg-1·d-1,n=11),atRA1 group (atRA of 5 mg·kg-1·d-1,n=10) and atRA2 group (atRA of 10 mg·kg-1·d-1,n=11).Sham group (soybean oil,1 mL·kg-1·d-1,n=7) served as a nomal control.Rats were treated by intragastric gavage once a day for 12 weeks. Serum creatinine concentration and 24 hours urinary albumin excretion were measured.The renal tubulointerstitial fibrosis was scored on renal sections with VG staining.The expression levels of α-smooth muscle actin (α-SMA) and  plasminogen activator inhibitor-1 (PAI-1) in renal cortex were examined by Western blot.Results  Treatment of atRA decreased the elevated levels of urinary albumin excretion and serum creatinine concentration in 5/6 nephrectomized rats at 14 weeks after operation (all P<0.05).Renal tubulointerstitial fibrosis score in rats with 5/6 nephrectomy was markedly decreased after atRA administration (P<0.01).The increases in expressions of α-SMA and PAI-1 in renal cortex in rats with 5/6 nephrectomy were significantly downregulated by atRA treatment (all P<0.05).Renal tubulointerstitial fibrosis score correlated well with the expression of α-SMA (r=0.7176,P<0.01) or with that of PAI-1 (r=0.8098,P<0.01).Conclusions  Treatment with atRA ameliorates renal tubulointerstitial fibrosis in rats with 5/6 nephrectomy by decreasing both proteinuria and protein expressions of α-SMA and PAI-1 in renal cortex.