The Effect of The Coadministration of Vitamin E in Cyclosporine A(CsA) Induced Acute Nephrotoxicity in Rats

Shin, Eun Seong; Kim, Young Wook; Kim, Yong Jin; Park, Yong Hoon

Abstract

Cyclosporine A(CsA) induced nephrotoxicity is a common clinical problem in the patients who underwent organ transplantation and subsequent immunosuppressive therapy. The precise pathophysiology of CsA induced nephrotoxicity still remains uncertain though many hypothesized mechanisms were reported. Therefore, no effective strategy is currently available to counter the nephrotoxic effects of CsA while cyclosporine G or cyclosporine microemulsion was tried to reduce the toxic effects. Recently, CsA was reported to induce lipid peroxidation in renal cortical mitochondria, which may cause mitochondrial damage. To examine the hypothesis of lipid peroxidation in the pathogenesis of acute CsA induced nephrotoxicity, antioxidant vitamin E was co-administerated in the CsA induced acute nephrotoxicity. Sprague Dawley male rats weighing from 250 to 400 gm were heminephrectomized 7 days prior to the experiments. The rats were divided into 3 groups and each group consisted of 7 rats. In group I(control group), the rats were given sterilized olive oil intraperitoneally, in group II(CsA group), CsA 50 mg/kg of body weight/day intraperitoneally, and in group III(CsA with vitamin E), CsA 50 mg/kg of body weight/day intraperitoneally with vitamin E 10 mg/kg of body weight/day intramuscularly for 7 days respectively. From the 6th day, all experimental animals were placed in a metabolic cage collecting urine for the measurement of 24-hours urine thromboxane B2, the metabolite of thromboxane A2. On the 7th day, at the sacrifice of the experimental animals, blood samplings for the measurement of blood CsA level and serum creatinine and left nephrectomy for morphological study were performed. Comparison of mean serum creatinine levels between 2 study groups revealed 171.7+/-164.2 micro Mol/L in group II and 53.4+/-13.9 micro Mol/L in group III(p<0.05). Mean 24-hour urine thromboxane B2 levels were 39.0+/-6.9 ng/24 hours in group I, 74.8+/-22.6 ng/24 hours in group II, and 34.5+/-8.0 ng/24 hours in group III. Urine thromboxane B2 was significantly(p=.0026) lower in group III. The differences of morphological changes in group II and III can be summarized as a diminution of PAS(+) granules under the light microscope and a diminution of the numbers of secondary lysosomes in the proximal tubular epithelial cell under the electron microscope. In conclusion, this animal study provides an evidence that CsA-induced acute nephrotoxicity is related with lipid peroxidation and the antioxidant, vitamin E was considered to ameliorate CsA-induced acute nephrotoxicity in rats.