Inhibition of calcineurin/NFAT pathway plays an essential role in renoprotective effect of tropisetron in early stage of diabetic nephropathy

Abstract

Recent studies have shown that calcineurin plays a central role in hypertrophy and extracellular matrix (ECM) accumulation in glomeruli at the early stages of diabetic nephropathy. Tropisetron is an effective antiemetic drug which also can potently inhibit calcineurin. The aim of this study was to investigate whether tropisetron can prevent glomerular hypertrophy and ECM expansion in early diabetic nephropathy. Streptozotocin (STZ)-induced diabetic rats were treated with tropisetron and cyclosporine A, a pharmacological calcineurin inhibitor, and the renal function and the expression of calcineurin and fibronectin were then assessed as well as nuclear localization of nuclear factor of activated T-cell c1 (NFATc1). 2 weeks after diabetes induction, all STZ-treated rats showed hyperglycemia, polyuria, body weight loss and renal dysfunction, as evidenced by increased glomerular filtration rate (GFR), along with a marked pathological changes in kidney. Calcineurin expression was increased in association with increased nuclear localization of the calcineurin substrate NFATc1 and fibronectin expression in glomeruli of diabetic rats. In parallel, the diabetic glomeruli became hypertrophic with an increase in kidney weight. Tropisetron, as potent as cyclosporine A, significantly ameliorated the early nephropathy symptoms, potentially through suppression of calcineurin expression, nuclear localization of NFATc1 and accumulation of fibronectin, and thereby reduced hypertrophy in glomeruli of diabetic rats.In conclusion, our results showed that tropisetron could ameliorate kidney injury in the early stage of diabetic nephropathy in rats. The renoprotective effects of tropisetron can be attributed, at least in part, to the suppression of diabetes-induced increases in calcineurin expression in kidney tissue.