Inhibitory effects of T/L-type calcium channel blockers on tubulointerstitial fibrosis in obstructed kidneys in rats.

摘要

OBJECTIVES: To examine the effect of L- and T/L-type calcium channel blockers on interstitial fibrosis in chronic unilateral ureteral obstruction (UUO). Tubulointerstitial fibrosis is a common outcome of several progressive renal diseases. Calcium channel blockers are widely used for the treatment of hypertension with renal diseases; however, the direct effect of calcium channel blockers on renal diseases independent of lowering blood pressure has not been fully elucidated. METHODS: Sprague-Dawley rats were divided into 3 treatment groups: (1) vehicle control; (2) nifedipine, an L-type calcium channel blockers; and (3) efonidipine, a T/L-type calcium channel blockers. Treatment was initiated 1 day before and continued until 6 days after creation of the UUO. RESULTS: Tubulointerstitial fibrosis in the obstructed kidney was significantly increased compared with that in the contralateral unobstructed kidney. Furthermore, the increased fibrosis was accompanied by increased fibrogenic signaling expressed by transforming growth factor beta1 and connective tissue growth factor mRNA levels, increased oxidative stress expressed by p22phox, p47phox and gp91phox mRNA level. Moreover, treatment with a nonhypotensive dose of efonidipine but not nifedipine in the obstructed kidney significantly suppressed the fibrogenic signaling and the oxidative stress, resulting in reduced tubulointerstitial fibrosis. The plasma aldosterone level in efonidipine-treated animals was increased compared with vehicle-treated animals, although not significantly. The increased plasma aldosterone level did not increase sgk-1 mRNA level in efonidipine but not in nifedipine treated animals. CONCLUSIONS: Treatment with efonidipine improved tubulointerstitial fibrosis more effectively than treatment with nifedipine in UUO. The antifibrogenic effect by efonidipine was obtained through suppression of fibrogenic signaling.