探讨罗格列酮对减轻环孢素A所致慢性肾毒性的作用及机制

目的 探讨罗格列酮(RGZ)对减轻环孢素A(CsA)所致慢性肾毒性的作用及机制.方法 选择健康、雄性SD大鼠,给予低盐饮食,饲养1周后,随机分成4组.(1)对照组(6只):除低盐饮食外,不给予任何处理;(2)岁格列酮组(6只):低盐饮食,并给予RGZ 5 mg·kg-1·d-1;(3)肾毒性模型组(8只):低盐饮食,并给予CsA 15 mg·kg-1·d-1;(4)治疗十预组(8只):低盐饮食,并给予CsA15 mg·kg-1·d-1和RGZ 5 mg·kg1·d-1.于实验的第2周,每组随机处死3只大鼠,实验的第5周,处死其余的大鼠.检测各组大鼠处死前的内生肌酐清除率(Ccr)和血清白蛋白(ALB)含量;观察各组肾组织的病理学变化;检测各组肾组织中基质金属蛋白酶-9(MMP-9)及金属蛋白酶组织抑制因子-1(TIMP-1)的表达水平.结果 实验第2周,肾毒性模型组和治疗干预组的Ccr及ALB含量均显著下降,第5周下降更为显著,与对照组和罗格列酮组比较,差异有统计学意义(P<0.05);治疗干预组Ccr及ALB下降程度较肾毒性模型组轻,第5周时的Ccr与肾毒性模型组比较,差异有统计学意义(P<0.05).实验第2周,肾毒性模犁组的肾问质可见大量炎症细胞浸润,第5周时,肾小管明显萎缩,肾小球硬化,问质纤维化程度加重;治疗十预组肾组织的损害程度明显较肾毒性模型组轻.肾毒性模型组和治疗十预组在实验的第2周和第5周MMP-9和TIMP-1的表达水平均较对照组和罗格列酮组明显增加(P<0.05),但治疗干预组MMP-9和TIMP-1的表达水平均显著低于同时段肾毒性模型组(P<0.05).结论 罗格列酮可显著降低CsA所致慢性肾毒性大鼠MMP-9和TIMP-1的表达水平,从而减轻CsA对肾脏的慢性毒性作用.

Rosiglitazone alleviated chronic cyclosporine nephropathy and the underlying mechanism

Objective To study the preventive effects of rosiglitazone (RGZ) on chronic cyclosporine nephropathy (CCN) and the underlying mechanism.Methods Healthy male SD rats fed on LSD for one week were randomly assigned to normal group, RGZ (5 mg·kg-1 · d-1) group, cyclosporine A (15 mg·kg-1·d-1) group, RGZ treatment (cyclosporine A, 15 mg·kg-1·d-1 + RGZ, 5 mg·kg1·d-1) group after CAZN.Three rats in each group were sacrificed randomly 2 weeks later, and the rest were killed at the end of the experiment (5 weeks later).Serum creatine (Ccr) and albumin (ALB) were determined.Interstitial mononuclear cells were counted in HE staining, and interstitial fibrosis was calculated in Masson's staining.RT-PCR was used to detect the expression of MMP-9 and TIMP-1 in renal tissues of rats.Results Ccr in CsA-treated rats was decreased significantly (P<0.05), and RGZ ameliorated the decrease of Ccr markedly at the 5th week (P< 0.05).The serum level of AIB was decreased markedly in CsA-treated rats (P<0.05), but RGZ failed to improve the ALB neither at the 2nd nor at 5th week (P>0.05).The amount of interstitial mononuclear cells infiltrated was increased markedly in CsA-treated rats at the 2nd week (P>0.05).Tube atrophy, globule sclerosis and interstitial fibrosis were observed with Masson's staining in CsA-treated rats, progressed with time, and peeked at the 5th week.RGZ significantly alleviated fibrosis at the 5th week (P<0.05).In comparison with normal group, the expression of MMP-9 and TIMP-1 in CCN and treatment groups was markedly increased (P<0.05).In comparison with CCN group, the expression of MMP-9 and TIMP-1 was significantly decreased in treatment groups (P<0.05).Conclusion RGZ may alleviate chronic cyclosporine nephropathy by decreasing the expression of MMP-9 and TIMP-1.