Bae Eun Hui, Lee JongUn, Ma Seong Kwon, Kim In Jin, Frøkiaer Jørgen, Nielsen Søren, Kim Sun Young, Kim Soo Wan
Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.
Nephrol Dial Transplant. 2009 Sep;24(9):2692-700. doi: 10.1093/ndt/gfp176. Epub 2009 Apr 17.
Cisplatin-induced nephropathy has been related to increased lipid peroxide formation and decreased activity of antioxidant enzymes in the kidney. The present study aimed to examine whether treatment with alpha-lipoic acid (alpha-LA) prevents the cisplatin-induced nephrotoxicity.
Two groups of rats were treated with cisplatin, one of which being cotreated with alpha-LA. The control group was treated with vehicle only. Four days later, the expression of aquaporins and sodium transporters was determined in the kidney by immunoblotting and immunohistochemistry. The arginine vasopressin-stimulated generation of cAMP was measured by radioimmunoassay. The expression of nitric oxide synthases (NOS) was determined by immunoblotting. The mRNA expression of endothelin-1 (ET-1) and tumour necrosis factor (TNF)-alpha was measured by real-time PCR. Apoptosis was examined by TUNEL staining.
Following the treatment with cisplatin, urinary volume and fractional excretion of sodium increased. Accordingly, the expression of aquaporins 1-3, Na,K-ATPase, NHE3 and NKCC2 was decreased. The expression of adenylyl cyclase VI and vasopressin-stimulated cAMP generation was decreased. The expression of inducible NOS was increased, while that of endothelial NOS decreased. The ET-1 expression was increased. TUNEL-positive cells were increased, in association with an increased expression of TNF-alpha. alpha-LA treatment prevented dysregulation of these parameters and resumed the renal function.
alpha-LA may prevent the cisplatin-induced nephrotoxicity, possibly through preserving the activities of NO and ET systems and inhibiting the development of apoptosis.
顺铂诱导的肾病与肾脏中脂质过氧化物形成增加及抗氧化酶活性降低有关。本研究旨在探讨α-硫辛酸（α-LA）治疗是否能预防顺铂诱导的肾毒性。
两组大鼠接受顺铂治疗，其中一组同时接受α-LA治疗。对照组仅接受赋形剂治疗。四天后，通过免疫印迹和免疫组织化学法测定肾脏中水通道蛋白和钠转运体的表达。通过放射免疫分析法测定精氨酸加压素刺激的环磷酸腺苷（cAMP）生成。通过免疫印迹法测定一氧化氮合酶（NOS）的表达。通过实时聚合酶链反应（PCR）测定内皮素-1（ET-1）和肿瘤坏死因子（TNF）-α的mRNA表达。通过末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色检测细胞凋亡。
顺铂治疗后，尿量和钠分数排泄增加。相应地，水通道蛋白1-3、钠钾-ATP酶、钠氢交换体3（NHE3）和钠钾氯协同转运蛋白2（NKCC2）的表达降低。腺苷酸环化酶VI的表达和加压素刺激的cAMP生成降低。诱导型NOS的表达增加，而内皮型NOS的表达降低。ET-1表达增加。TUNEL阳性细胞增加，同时TNF-α表达增加。α-LA治疗可防止这些参数的失调并恢复肾功能。
α-LA可能通过维持一氧化氮和内皮素系统的活性并抑制细胞凋亡的发展来预防顺铂诱导的肾毒性。
