Intrarenal angiotensin II augmentation in angiotensin II dependent hypertension.

In several models of angiotensin II (ANG II) dependent hypertension, intrarenal ANG II levels increase to a much greater extent than the circulating levels even though the renal renin levels are decreased. The 2-kidney-1-clip (2K1C) Goldblatt rat model is particularly intriguing because hypertension develops in the presence of an intact kidney which would be expected to maintain sodium balance and protect against hypertension. Although the non-clipped kidney becomes renin depleted, it exhibits enhanced microvascular reactivity and increased tubular fractional sodium reabsorption. The non-clipped kidney ANG II content is either elevated or unchanged and proximal tubular fluid ANG II concentrations are not suppressed compared to the nanomolar concentrations found in normal rats. These results suggest that intrarenal ANG II content can be regulated independently of renal renin content. A similar hypertensive process occurs in rats infused chronically with low doses of ANG II. Renal ANG II content increases over 14 days to a greater extent than the circulating concentrations. Functionally, ANG II infused rats demonstrate reduced sodium excretion and marked suppression of pressure natriuresis. These ANG II dependent influences on kidney function contribute to the maintenance of hypertension. Renal augmentation of ANG II, hypertension, and suppressed sodium excretion are blocked by AT1 receptor blockers. To study the mechanisms responsible for intrarenal ANG II augmentation, we infused a different form of ANG II (Val5 ANG II), that can be separated from endogenous ANG II by HPLC. These results indicated that the increased renal ANG II content was due to accumulation of circulating ANG II in addition to continued production of endogenous ANG II. The renal accumulation of Val5-ANG II was markedly reduced by concomitant treatment with the AT1 receptor blocker, losartan. In addition, we found an unchanged overall ANG II-AT1 receptor protein which probably contributes to the maintained ANG II dependent influences. Collectively, the data support the concept that there is internalization of ANG II through an AT1 receptor mediated process and that some of the internalized ANG II is protected from degradation. The augmented intrarenal ANG II coupled with sustained levels of AT1 receptors contribute to the continued ANG II dependent suppression of renal function and sodium excretion thereby maintaining the hypertension.