title: Involvement of N-type Ca(2+) channels in the fibrotic process of the kidney in rats.
abstract: N-type Ca(2+) channels are densely distributed in sympathetic nerves that innervate renal tubules. However, the role of N-type Ca(2+) channels in renal fibrosis remains unknown. To address this issue, we examined the difference between the effects of amlodipine (an L-type Ca(2+) channel blocker) and cilnidipine (a dual L/N-type Ca(2+) channel blocker) on fibrotic changes using a rat unilateral ureteral obstruction (UUO) model. The expression of both L-type and N-type Ca(2+) 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 Ca(2+) channels contribute to multiple steps of renal fibrosis, and its blockade may thus be a useful therapeutic approach for prevention of renal fibrosis.
authors: Department of Medicine and Clinical Science, Gunma University, Graduate School of Medicine, Maebashi, Japan.
authors: Keiichiro
authors: K
authors: Mishima
authors: Akito
authors: A
authors: Maeshima
authors: Masaaki
authors: M
authors: Miya
authors: Noriyuki
authors: N
authors: Sakurai
authors: Hidekazu
authors: H
authors: Ikeuchi
authors: Keiju
authors: K
authors: Hiromura
authors: Yoshihisa
authors: Y
authors: Nojima
mesh_terms: D000199:Actins / Q000378:metabolism; D017311:Amlodipine / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D007668:Kidney / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014517:Ureteral Obstruction / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D000199:Actins; D017311:Amlodipine; D015820:Cadherins; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; C498862:Acta2 protein, rat; C065927:cilnidipine