The Protective Effect of Febuxostat on Chronic Tacrolimus-Induced Nephrotoxicity in Rats

Abstract

Background: The use of calcineurin inhibitors is a well-known risk factor for hyperuricemia in kidney transplant recipients. We evaluated the effect of febuxostat (Fx), a new uric acid-lowering drug, on hyperuricemia and renal injury in an experimental model of chronic tacrolimus (Tac)-induced nephropathy. Methods: Chronic Tac nephropathy was induced by administering Tac (1.5 mg/kg/day) to rats on a low-salt diet (0.05%) with oxonic acid (OA, 2%, 0.2 g/kg/day) for 28 days. Two doses of Fx (5 and 10 mg/kg) were concomitantly administered with Tac or vehicle (Vh). We evaluated the effect of Fx on hyperuricemia by measuring serum uric acid (SUA) levels, fractional excretion of uric acid (FEUA), and urate transporters in Tac-induced nephropathy. The effects of Fx on Tac-induced renal injury were evaluated in terms of renal function and arteriolopathy, tubulointerstitial fibrosis, inflammation, and apoptosis. We evaluated oxidative stress as a protective mechanism via xanthine oxidase (XO) activity, and as a marker of oxidative stress (via evaluation of levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxy-2-hexenal (4-HHE)). Results: The Tac group showed higher SUA levels and lower FEUA than did the Vh group, but Fx treatment significantly decreased SUA levels in a dose-dependent manner, with an increase of FEUA at a high dose (10 mg/kg). Tac treatment increased urate-anion exchanger 1 and decreased organic anion transporter type 1 expression in renal tubular cells, but Fx treatment reversed the effects on those transporters. Impaired renal function and histological injury (interstitial fibrosis, inflammation, and arteriolopathy) in the Tac group were markedly improved by Fx administration. Increases in apoptotic cell death and activation of proapoptotic caspase-3 by Tac were remarkably decreased by Fx treatment. Tac administration increased the activity of XO in kidney tissue and serum, and the levels of 8-OHdG in urine and 8-OHdG and 4-HHE of kidney tissue, but combined treatment with Fx decreased the levels of these parameters. Conclusions: Fx is effective in controlling hyperuricemia and in preventing Tac-induced renal injury, via a reduction of oxidative stress. Therefore, a targeted therapy aimed at inhibiting uric acid by Fx may be a useful approach in the management of the progression of nephropathy in renal transplant patients treated with Tac.