Intrarenal Renin-Angiotensin System: Locally Synthesized or Taken up Via Endocytosis?

Abstract

See related article, pp 927–933 The renin–angiotensin system (RAS) has long been recognized to play a preeminent role in the control of blood pressure and the development of hypertension. There is a general consensus that both the circulating (endocrine) and the local (paracrine) RAS act together to regulate vascular tone, sympathetic outflow, renal tubular and vascular function, pressure natriuresis, and blood pressure. However, it has been difficult to dissect the specific contributions of the circulating versus the local RAS to the regulation of renal function because components of the RAS in the proximal tubule can be absorbed or taken up by endocytosis as well as synthetized locally. In this issue of Hypertension , Roksnoer et al1 used a variety of approaches to better define the origin of renin and prorenin found in the proximal tubule and urine. The existence of the intrarenal RAS is strongly supported by the observations that the concentrations of angiotensin I (Ang I) and II in proximal tubular fluid and in the kidney often exceed that of plasma, and components of the RAS in the kidney can be regulated independently from circulating levels.2 In addition, prorenin, angiotensinogen, and angiotensin-converting enzyme (ACE) are all synthetized in various nephron segments.2 Indeed, as summarized in Figure, Ang I and II as well as renin, prorenin, angiotensinogen, and ACE proteins are all expressed in the proximal tubule. Furthermore, prorenin and ACE proteins are localized in the cortical collecting duct. Prorenin, renin, angiotensinogen, and Ang II are also excreted and the levels in urine increase in some forms of hypertension and renal disease.3,4 The prevailing view is that circulating Ang I and II are filtered and reabsorbed in the proximal tubule. Ang II is also formed locally through the interactions of renin, angiotensinogen, and …