罗格列酮对实验性慢性环孢素肾病的作用

目的 探讨罗格列酮（RSG）对慢性环孢素肾病（CCN）大鼠模型的肾保护作用。 方法 低盐饮食基础上建立CCN大鼠模型，其中1组模型鼠用RSG同时灌胃。分别在实验开始后第14天和第35天处死动物，检测血浆和肾组织血管紧张素Ⅱ（AngⅡ）、AngⅡ1型受体(AT1R)、转化生长因子β1(TGF-β1)、细胞外调节蛋白激酶（p-ERK）、α-SMA和纤连蛋白（FN）的表达。在体外用不同浓度的CsA和RSG孵育NRK细胞。RT-PCR检测肾皮质TGF-β1，Western印迹分析检测FN、AT1R、p-ERK水平。 结果 RSG可改善环孢素A导致的大鼠肌酐清除率的下降（0.586±0.094）比(1.072±0.105)ml&#8226;min^-1&#8226;kg^-1，P < 0.01]、血浆和肾组织AngⅡ水平增加（P < 0.01）、肾间质单核细胞浸润（P < 0.01）、肾间质纤维化（1.707±0.019 比 2.335±0.022，P < 0.01）、肾组织α-SMA表达增加（P < 0.01）、肾皮质TGF-β1 mRNA水平增加（P < 0.01）、NRK细胞FN、AT1R和p-ERK蛋白水平增加（P < 0.05）。 结论 RSG可能通过减轻炎细胞浸润、影响AngⅡ作用和下调TGF-β1等途径减轻CsA所致的肾组织损伤。

Effects of rosiglitazone on experimental chronic cyclosporine nephropathy

Objective To observe the protective effects of rosiglitazone (RSG) on nephrotoxicity induced by cyclosporine A (CsA) in rats and normal rat kidney cells (NRK). Methods Three groups of adult male Sprague-Dawley rats that received sodium-depletion diet (SD, 0.037% sodium) were studied. Controls (n = 12) were fed with SD and vehicle; CsA-treated rats (n = 15) were given SD and CsA (15 mg·kg^-1·d^-1, i.h.) to establish chronic CsA nephropathy(CCN); rosiglitazone-treated rats (n = 15) were given SD and CsA (15 mg·kg^-1·d^-1, i.h.) and RSG (5 mg·kg^-1·d^-1) by gavage. Six rats of each group were sacrificed at day 14 and others were sacrificed at the end of the study (day 35). Blood, urine and tissue sample were collected at the two time points. NRK cells were cultured and incubated with CsA and RSG at different concentrations. Kidneys underwent light microscopy by Masson staining to observe the renal interstitial fibrosis index and immunohistochemistry for α-SMA and TGF-β1. Renal cortex TGF-β1 mRNA expression was measured by RT-PCR. Phosphorylation-extracellular signal regulated kinase (p-ERK), fibronectin (FN) and type 1 receptor of angiotensin Ⅱ (AT1R) were measured by Western blot. Plasma and intrarenal Ang Ⅱ activity were measured by radioimmunology. Results Compared with control, CsA increased mononuclear cells infiltration in the interstitium at day 14, caused a significant decrease in the level of creatinine clearance rate, and induced tubulointerstitial fibrosis at day 35 (P < 0.01). These lesions of CCN were significantly ameliorated by RSG (P < 0.05). The overactiviated plasma and intrarenal angiotensin Ⅱ and the overexpression of fibronectin, α-SMA and TGF-β1 induced by CsA were alleviated by RSG (P < 0.05). Meanwhile, a significant increase of expression levels of TGF-β1, FN, p-ERK, AT1R protein in NRK cells by CsA was found (P < 0.01). Treatment with RSG for 24 h attenuated these upregulation (P< 0.01). Conclusions Rosiglitazone, possibly by activating PPARγ, delays the progression of CCN. These effects were linked to decreased expression of TGF-β1, α-SMA and ECM. PPARγ may be a new target for the prevention and treatment of CCN.