Navar L Gabriel
Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, Louisiana, USA.
Kidney Int Suppl (2011). 2013 Dec;3(4):321-325. doi: 10.1038/kisup.2013.67.
Various models of experimental hypertension and clinical examples of increased renin formation from a stenotic kidney or a juxtaglomerular cell tumor have shown that increased circulating angiotensin II (Ang II) stimulates the intrarenal/intratubular renin-angiotensin system (RAS) that elicits renal vasoconstriction, enhanced tubular sodium reabsorption, and progressive development of hypertension and renal injury. The enhanced intrarenal Ang II activity is due to both receptor-mediated Ang II uptake and Ang II type 1 (AT1) receptor-mediated stimulation of renal angiotensinogen (AGT) mRNA and protein by proximal tubule cells. The increased AGT secretion leads to local formation of Ang II and spillover of AGT into the distal nephron segments as reflected by increased AGT excretion in the urine, which provides an index of intrarenal RAS activity. In clinical studies, increased urinary excretion of AGT has been demonstrated in hypertension, type 1 and type 2 diabetes mellitus, and several types of chronic kidney diseases. In addition, renin secretion from principal cells of the collecting ducts is increased by AT1 receptor activation and acts on AGT from the proximal tubule to form more Ang I. Renin and/or (pro)renin activity is enhanced by binding to the (pro)renin receptor (PRR) on intercalated cells or secreted as soluble PRR contributing further to AGT cleavage, thus making more substrate available for Ang II conversion by local angiotensin-converting enzyme. The augmented intratubular Ang II concentrations together with elevated renal interstitial Ang II concentrations contribute to sustained stimulation of sodium reabsorption, vasoconstriction, development of hypertension, and progressive renal injury and fibrosis.
多种实验性高血压模型以及因狭窄肾脏或肾小球旁细胞瘤导致肾素生成增加的临床实例均表明，循环中血管紧张素II（Ang II）水平升高会刺激肾内/肾小管内肾素-血管紧张素系统（RAS），引发肾血管收缩、肾小管钠重吸收增强，以及高血压和肾损伤的逐步发展。肾内Ang II活性增强既归因于受体介导的Ang II摄取，也归因于近端小管细胞通过血管紧张素II 1型（AT1）受体介导刺激肾血管紧张素原（AGT）的mRNA和蛋白质。AGT分泌增加导致Ang II在局部形成，并使AGT溢入远端肾单位节段，尿液中AGT排泄增加即反映了这一点，这提供了肾内RAS活性的一个指标。在临床研究中，已证实在高血压、1型和2型糖尿病以及几种慢性肾脏病中，尿AGT排泄增加。此外，集合管主细胞的肾素分泌通过AT1受体激活而增加，并作用于近端小管的AGT以形成更多的血管紧张素I。肾素和/或（前）肾素活性通过与闰细胞上的（前）肾素受体（PRR）结合而增强，或作为可溶性PRR分泌，进一步促进AGT裂解，从而为局部血管紧张素转换酶将AGT转化为Ang II提供更多底物。肾小管内Ang II浓度升高以及肾间质Ang II浓度升高共同导致对钠重吸收、血管收缩、高血压发展以及进行性肾损伤和纤维化的持续刺激。
