NF-κB在大鼠CsA肾毒性中的作用

Role of nuclear factor-κB in cyclosporin A-induced nephrotoxicity in rats

目的探讨NF-κB在环孢素A(CsA)肾毒性中的作用及与TGFβ-1、caspase-3和细胞凋亡的关系。方法Wist-ar雄性大鼠64只随机分成4组:溶剂对照组,二硫代氨基甲酸吡咯烷(PDTC)组,CsA组,CsA+PDTC组。动物每日皮下注射CsA15mg/kg,或溶剂、PDTC各100mg/kg。4周后取肾脏,检测血BUN、Cr、尿NAG酶和尿常规。HE、TUNEL、免疫组化观察。结果光镜下观察到明显的CsA慢性肾损伤。CsA组较其他组血BUN、Cr,尿NAG酶显著增高,尿常规有蛋白尿,尿比重降低;而CsA+PDTC组与对照组比较无差异。TUNEL检测到CsA组细胞凋亡及免疫组化检测有NF-κB、TGF-β1和caspase-3的表达。PDTC阻断NF-κB后,TGF-β1和caspase-3表达显著减弱。CsA+PDTC组与对照组比较无明显变化。结论CsA可致肾细胞凋亡。阻断NF-κB后凋亡明显减少,肾损伤减轻。提示CsA肾毒性与NF-κB的激活有关。

Objective To ascertain the role of NFκB and relationship among TGFβ1, caspase-3 and apoptosis in CsA-induced nephrotoxicity. Methods Sixty-four wistar male rats were randomly divided into 4 groups： Vehicle, PDTC ,CsA and CsA ＋ PDTC group. The animals were daily subcutaneously injected either with CsA （ 15 mg/kg） or vehicle/PDTC （100 mg/kg）. Four weeks later, BUN, serum creatinine, NAG and urine routine were examined. The kidneys were processed for light microscopy, immunohistochemistry and TENUL. Results A rat model of CsA-induced nephrotoxicity was established. CsA group showed significant increase in BUN, SCr and urine NAG compared with the controls, whereas CsA ＋ PDTC group did not. Apoptosis is observered by TUNEL and the expressions of NF-κB, TGF-β1, caspase-3 increased significantly in CsA group compared with conrtol group. Whereas, both the apoptosis and the expressions of these proteins significantly decreased in rats treated with PDTC. Conclusion Apoptosis is induced in the CsA-induced chronic nephrotoxicity. Inhibition of NF-κB activation blockaded apoptosis and ameliorated CsA-induced chronic nephrotoxicity. The results suggest that NF-κB plays important roles in the progression of chronic CsA nephrotoxicity.