Involvement of N-type Ca2+channels in the fibrotic process of the kidney in rats

Abstract

N-type Ca2+channels are densely distributed in sympathetic nerves that innervate renal tubules. However, the role of N-type Ca2+channels in renal fibrosis remains unknown. To address this issue, we examined the difference between the effects of amlodipine (an L-type Ca2+channel blocker) and cilnidipine (a dual L/N-type Ca2+channel blocker) on fibrotic changes using a rat unilateral ureteral obstruction (UUO) model. The expression of both L-type and N-type Ca2+channels was significantly upregulated in UUO kidneys compared with that in contralateral kidneys. There were no significant differences in mean blood pressure among the rats tested. Both amlodipine and cilnidipine significantly attenuated fibrotic changes in UUO kidneys. The antifibrotic effect of cilnidipine was more potent than that of amlodipine. Amlodipine as well as cilnidipine reduced type III collagen deposition, α-smooth muscle actin (α-SMA) expression, and interstitial cell proliferation. In addition, cilnidipine significantly reduced deposition of type I collagen and macrophage infiltration in UUO kidneys. With the use of in vivo bromodeoxyuridine labeling, label-retaining cells (LRCs) were identified as a population of tubular cells that participate in epithelial-mesenchymal transition after UUO. Some LRCs migrated into the interstitium, expressed α-SMA and vimentin, and produced several extracellular matrixes in UUO kidneys. The number of interstitial LRCs was significantly decreased by cilnidipine but not amlodipine. These data suggest that N-type Ca2+channels contribute to multiple steps of renal fibrosis, and its blockade may thus be a useful therapeutic approach for prevention of renal fibrosis.