Involvement of N-type Ca2+ channels in the fibrotic process of the kidney in rats
Involvement of N-type Ca2+ channels in the fibrotic process of the kidney in rats
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DOI：
10.1152/ajprenal.00561.2012
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发表时间：
2013-03-01
影响因子：
4.2
通讯作者：
Nojima, Yoshihisa
中科院分区：
文献类型：
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作者：
Mishima, Keiichiro;Maeshima, Akito;Nojima, Yoshihisa
三岛K，Maeshima A，Miya M，Sakurai N，Ikeuchi H，Hiromura K，Nojima Y. N型钙通道参与大鼠肾脏纤维化过程美国肾脏生理学杂志304：F665-F673，2013年。首次发表于2013年1月16日; doi：10.1152/ajprenal.00561.2012.- N-型Ca 2+通道密集分布在支配肾小管的交感神经中。然而，N型钙通道在肾纤维化中的作用仍然未知。为了解决这一问题，我们使用大鼠单侧输尿管梗阻（UUO）模型研究了L-type Ca 2+通道阻滞剂（L-type Ca 2 + channel blocker）和西尼地平（cilnidipine）（L/N-type Ca 2 + channel blocker）对纤维化变化的影响之间的差异。与对侧肾脏相比，UUO肾脏L型和N型Ca 2+通道的表达均显著上调。受试大鼠的平均血压无显著差异。阿托伐他汀和西尼地平均显著减弱UUO肾脏的纤维化变化。西尼地平的抗肝纤维化作用强于西尼地平。阿米替林和西尼地平可减少III型胶原沉积、α-平滑肌肌动蛋白（α-SMA）表达和间质细胞增殖。此外，西尼地平显着减少沉积的I型胶原蛋白和巨噬细胞浸润UUO肾脏。使用体内溴脱氧尿苷标记，标记保留细胞（LRC）被确定为参与UUO后上皮-间充质转化的肾小管细胞群。一些LRC迁移到肾小管，表达α-SMA和波形蛋白，并在UUO肾脏中产生几种细胞外基质。西尼地平可显著减少间质LRC的数量，但西尼地平对间质LRC的数量无影响。这些数据表明，N-型Ca 2+通道有助于肾纤维化的多个步骤，因此其阻断可能是预防肾纤维化的有用治疗方法。
Mishima K, Maeshima A, Miya M, Sakurai N, Ikeuchi H, Hiromura K, Nojima Y. Involvement of N-type Ca2+ channels in the fibrotic process of the kidney in rats. Am J Physiol Renal Physiol 304: F665-F673, 2013. First published January 16, 2013; doi:10.1152/ajprenal.00561.2012.-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, alpha-smooth muscle actin (alpha-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 alpha-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.