Regulation of Intrarenal Angiotensin II in Hypertension

Abstract

Abstract-Intrarenal angiotensin II (Ang II) is regulated by several complex processes involving formation from both systemically delivered and intrarenally formed substrate, as well as receptor-mediated internalization. There is substantial compartmentalization of intrarenal Ang II, with levels in the renal interstitial fluid and in proximal tubule fluid being much greater than can be explained from the circulating levels. In Ang II-dependent hypertension, elevated intrarenal Ang II levels occur even when intrarenal renin expression and content are suppressed. Studies in Ang II-infused rats have demonstrated that augmentation of intrarenal Ang II is due, in part, to uptake of circulating Ang II via an Ang II type 1 (AT 1 ) receptor mechanism and also to sustained endogenous production of Ang II. Some of the internalized Ang II accumulates in the light and heavy endosomes and is therefore potentially available for intracellular actions. The enhanced intrarenal Ang II also exerts a positive feedback action to augment intrarenal levels of angiotensinogen (AGT) mRNA and protein, which contribute further to the increased intrarenal Ang II in hypertensive states. In addition, renal AT 1 receptor protein and mRNA levels are maintained, allowing increased Ang II levels to elicit progressive effects. The increased intrarenal Ang II activity and AGT production are associated with increased urinary AGT excretion rates. The urinary AGT excretion rates show a clear relationship to kidney Ang II content, suggesting that urinary AGT may serve as an index of Ang II-dependent hypertension. Collectively, the data support a powerful role for intrarenal Ang II in the pathogenesis of hypertension. Key Words: renin-angiotensin system Ⅲ angiotensinogen Ⅲ receptors, angiotensin Ⅲ hypertension, experimental I t is an honor and a privilege to be selected to present the Arthur C. Corcoran Memorial Lecture and I greatly appreciate this recognition that has been given to our research group. We all realize, however, that this year is very different for our country. The terrorist attacks have burned the date of September 11, 2001, indelibly in our minds. In the light of these tragic events, it has been difficult to move forward with the ordinary business of our lives. Compared with the sacrifices of the victims and their families, our activities have seemed irrelevant. Aside from moral and financial support, there is little that we personally can do. As scientists, however, we are comforted by the conviction that what we do collectively provides significant long-term benefits to the health and well-being of our citizens. Thus, going about our business and minimizing the disruptions is the most positive response that we can make. In doing so, however, we keep in mind that others less fortunate lost their lives or their loved ones while they were going about the ordinary business of their lives.As a renal physiologist, receiving this Corcoran Award is particularly meaningful because Dr. Corcoran performed so many interesting studies related to ...

Renal Renin-Angiotensin System

“…This effect was blocked by either saralasin or losartan indicating that this effect also involves AT1 receptor activation [68]. These findings, together with the demonstration that AT receptors are present on the luminal membranes of distal nephron segments [22,69] indicate that luminal Ang II plays an important role in the regulation not only of proximal reabsorption rate but also of distal tubular reabsorptive function [52]. Peti-Peterdi et al [70] demonstrated that Ang II directly stimulates epithelial sodium channel activity in the cortical collecting duct via AT1R.…”

“…The intrarenal content of Ang II is not distributed in a homogenous manner but is compartmentalized in both a regional and segmental manner [52]. It has been reported that Ang II is present at high concentrations in renal interstitial fluid (RIF) thus contributing to the disproportionately high total Ang II levels in the kidney [52].…”

“…It has been reported that Ang II is present at high concentrations in renal interstitial fluid (RIF) thus contributing to the disproportionately high total Ang II levels in the kidney [52]. Earlier measurements of renal lymph suggested that RIF Ang II concentrations were much higher than arterial or renal venous plasma concentrations [53].…”

“…These results demonstrate that there is ACE activity in the interstitial compartment. However, the failure of ACE inhibitors to reduce endogenous RIF Ang II concentrations substantially suggests that much of the RIF Ang II is formed at sites not readily accessible to ACE inhibitors or is formed via non-ACE-dependent pathways such as cathepsin, chymase or tonin [52]. It was also demonstrated that the RIF Ang II levels in Ang II-infused hypertensive rats are augmented above control [56] (fig.…”

Quantification of human angiotensinogen by a novel sandwich ELISA

“…The renin-angiotensin system plays an important role in blood pressure regulation and electrolyte homeostasis [5,[13][14][15]. In recent years, the focus of interest on the role of the reninangiotensin system in the regulation of arterial pressure and in the pathophysiology of hypertension has changed to a main emphasis on the role of the local/tissue renin-angiotensin systems in specific tissues [4].…”