First Department of Medicine, Hamamatsu University School of Medicine, Japan.
Am J Physiol Renal Physiol. 2012 Jul 1;303(1):F130-8. doi: 10.1152/ajprenal.00275.2011. Epub 2012 Apr 11.
Despite suppression of the circulating renin-angiotensin system (RAS), high salt intake (HSI) aggravates kidney injury in chronic kidney disease. To elucidate the effect of HSI on intrarenal RAS, we investigated the levels of intrarenal prorenin, renin, (pro)renin receptor (PRR), receptor-mediated prorenin activation, and ANG II in chronic anti-thymocyte serum (ATS) nephritic rats on HSI. Kidney fibrosis grew more severe in the nephritic rats on HSI than normal salt intake. Despite suppression of plasma renin and ANG II, marked increases in tubular prorenin and renin proteins without concomitant rises in renin mRNA, non-proteolytically activated prorenin, and ANG II were noted in the nephritic rats on HSI. Redistribution of PRR from the cytoplasm to the apical membrane, along with elevated non-proteolytically activated prorenin and ANG II, was observed in the collecting ducts and connecting tubules in the nephritic rats on HSI. Olmesartan decreased cortical prorenin, non-proteolytically activated prorenin and ANG II, and apical membranous PRR in the collecting ducts and connecting tubules, and attenuated the renal lesions. Cell surface trafficking of PRR was enhanced by ANG II and was suppressed by olmesartan in Madin-Darby canine kidney cells. These data suggest the involvement of the ANG II-dependent increase in apical membrane PRR in the augmentation of intrarenal binding of prorenin and renin, followed by nonproteolytic activation of prorenin, enhancement of renin catalytic activity, ANG II generation, and progression of kidney fibrosis in the nephritic rat kidneys on HSI. The origin of the increased tubular prorenin and renin remains to be clarified. Further studies measuring the urinary prorenin and renin are needed.
尽管抑制了循环肾素-血管紧张素系统（RAS），高盐摄入（HSI）仍会加重慢性肾脏病的肾脏损伤。为了阐明 HSI 对肾内 RAS 的影响，我们研究了高盐摄入的慢性抗胸腺细胞血清（ATS）肾炎大鼠肾内前肾素、肾素、（前）肾素受体（PRR）、受体介导的前肾素激活和 ANG II 的水平。与正常盐摄入相比，HSI 组肾炎大鼠的肾脏纤维化更为严重。尽管抑制了血浆肾素和 ANG II，但在 HSI 组肾炎大鼠中观察到肾小管前肾素和肾素蛋白显著增加，而肾素 mRNA、非蛋白水解激活的前肾素和 ANG II 没有相应增加。在 HSI 组肾炎大鼠中，PRR 从细胞质重新分布到顶膜，同时观察到非蛋白水解激活的前肾素和 ANG II 升高。在 HSI 组肾炎大鼠的集合管和连接小管中，OLMESARTAN 降低了皮质前肾素、非蛋白水解激活的前肾素和 ANG II，以及顶膜 PRR，并减轻了肾脏病变。在 Madin-Darby 犬肾细胞中，ANG II 增强了 PRR 的细胞表面转运，OLMESARTAN 抑制了 PRR 的细胞表面转运。这些数据表明，ANG II 依赖性增加顶膜 PRR 参与了肾内前肾素和肾素结合的增强，随后是前肾素的非蛋白水解激活、肾素催化活性的增强、ANG II 的生成以及 HSI 组肾炎大鼠肾脏纤维化的进展。肾小管前肾素和肾素增加的来源仍有待阐明。需要进一步研究测量尿前肾素和肾素。
