Trimetazidine Prevents Renal Fibrosis Induced by Cyclosporine A in Wister Rats

Cyclosporine A (CyA), an immunosuppressant administered to transplant patients, causes adverse effects such as nephrotoxicity and hepatotoxicity. In kidney slices of rats treated with 25 mg/kg/day of CyA we observed interstitial fibrosis. Ultrastructure revealed edematized mitochondria with loss of internal structure. In previous work with Trimetazidina (TMZ), cytoprotective drug used in cardiac patients, we found that TMZ prevents CyA toxicity. The pretreatment in wister rats with 20 mg/kg/day of TMZ during 20 days and them simultaneously TMZ with cyclosporine A for 120 days, counteracts the interstitial fibrosis.
The aim of this work is to elucidate the effect of TMZ on interstitial fibrosis and interpret its mechanism.
Four groups of eight male Wister rats were prepared. A, control; B, 25 mg/Kg/day CyA; C, 20 mg/Kg/day TMZ +25 mg/Kg/day CyA and D, 20 mg/Kg/day TMZ for 20 days and then TMZ 20 mg/Kg/day + CyA 25 mg/Kg/day. The experiment lasted 140 days. Slices of rats treated with CyA revealed fibrosis, which was quantified using Image Pro-Plus software (NIH). Immunohistochemical techniques evidenced Collagen type I, Transforming Growth Factor β1 (TGF-β1) and Monocyte Chemoattractant Protein-1 (MCP-1). However, pretreatment with TMZ for 20 days and then with CyA + TMZ prevented fibrosis and immunohistochemistry was negative for the markers studied. We concluded that TMZ protects the cells against the changes produced by the CyA-induced oxygen deficit. TMZ could offset ATP synthesis caused by the chronic administration of CyA. TMZ optimizes the energetic metabolism of the ischemic cell through a metabolic exchange (“switch”) between the fatty acid and glucose oxidation. In theory TMZ would reduce strongly the fatty acid oxidation towards glucose, without affecting the mitochondrial respiratory chain efficiency. Furthermore, TMZ increases the production of phospholipids in the mitochondrial membranes, which confers stability to these structures. In previous work check the effect of CyA on the complex I and II of the mitochondrial respiratory chain located in mitochondrial membranes which are the target of the toxic action of CyA.