Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats
Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats
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DOI：
10.1152/ajprenal.00197.2009
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发表时间：
2009-09-01
影响因子：
4.2
通讯作者：
Nakano, Daisuke
中科院分区：
文献类型：
--
作者：
Du, Jun;Fan, Yu-Yan;Nakano, Daisuke
杜J，范YY，Hitomi H，Kiyomoto H，Kimura S，Kong CZ，Noma T，Kohno M，Nishiyama A，中野D.盐皮质激素受体阻断剂和钙通道阻断剂对大鼠肾小球和间质损伤的肾脏保护作用不同。美国肾脏生理学杂志297：F802-F808，2009年。首次发表于2009年6月17日; doi：10.1152/ajprenal.00197.2009。我们假设盐皮质激素受体拮抗剂依普利酮和钙通道阻滞剂依普利酮的联合治疗通过不同的机制在Dahl盐敏感性（DS）高血压大鼠中发挥更好的肾脏保护作用。DS大鼠喂食高盐饮食（4%NaCl）10周，并在盐喂食2周后给予溶剂（n = 12）、依普利酮（50 mg.kg（-1）.day（-1），po，n = 12）、氨氯地平（3 mg.kg（-1）.day（-1），po，n = 12）或依普利酮加氨氯地平（n = 12）。溶剂处理的DS大鼠出现蛋白尿，依普利酮或依普利酮可减轻蛋白尿。有趣的是，依普利酮减轻肾小球硬化和足细胞损伤，但依普利酮没有。相反，用依普利酮治疗显著改善了间质纤维化，而依普利酮的作用很小。联合治疗显着改善蛋白尿，肾小球硬化，足细胞损伤，间质纤维化在DS大鼠。通过哌莫硝唑、血管内皮生长因子表达和管周内皮细胞密度估计的肾缺氧被盐喂养加剧。氨氯地平，无论是作为单一疗法或联合疗法，改善了肾缺氧，而依普利酮治疗没有效果。总之，依普利酮和依普利酮均能减轻高盐喂养DS大鼠的肾损伤，但这两种药物的肾保护作用靶点不同，依普利酮主要作用于肾小球，依普利酮主要作用于肾小球。依普利酮和依普利酮的组合改善高盐喂养的DS大鼠的肾损伤比任何单一疗法更有效，大概是通过实现自己的肾保护作用。
Du J, Fan YY, Hitomi H, Kiyomoto H, Kimura S, Kong CZ, Noma T, Kohno M, Nishiyama A, Nakano D. Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats. Am J Physiol Renal Physiol 297: F802-F808, 2009. First published June 17, 2009; doi:10.1152/ajprenal.00197.2009.-We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n = 12), eplerenone (50 mg.kg(-1).day(-1), po, n = 12), amlodipine (3 mg.kg(-1).day(-1), po, n = 12), or eplerenone plus amlodipine (n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.