The role of circulating angiotensin II on the contralateral kidney in the pathogenesis of two-kidney, one-clip Goldblatt hypertension
Description
Compromised renal perfusion results in the development of hypertension through the activation of the renin-angiotensin system. The model utilized in these experiments, the two-kidney, one-clip (2K1C) Goldblatt rat, uniquely permits the simultaneous examination of the response of the clipped kidney to impaired blood flow and the effects of hypertension, and of the stimulated levels of angiotensin II (Ang II) on the contralateral kidney. Although not the initial causative factor, the otherwise normal contralateral kidney plays a permissive role in the development of hypertension These investigations delineated the singular role of elevated circulating Ang II levels on the contralateral kidney in the pathogenesis of 2K1C hypertension. By infusing exogenous Ang II via an osmotic minipump, the clipped kidney was supplanted as the source of elevated circulating Ang II levels. Plasma Ang II levels observed in the 2K1C rats during the developmental phase of hypertension were simulated by the exogenous subcutaneous administration of Ang II at 40 ng/min and resulted in a comparable blood pressure profile and systemic Ang II levels, demonstrating that similar levels of circulating Ang II result in a similar blood pressure response The data further demonstrate that the elevated levels of circulating Ang II result in an increase in the intrarenal Ang II content, despite marked suppression of intrarenal and plasma renin, and support the hypothesis that enhanced endogenous Ang II generation occurs de novo via a renin-independent, positive amplification mechanism and may involve other enzymes known to metabolize angiotensinogen to angiotensin in the kidney Renal function studies did not demonstrate significant differences in renal hemodynamic or excretory parameters, despite differences in blood pressure and intrarenal Ang II levels. The acute administration of losartan caused a reduction in blood pressure without significant differences in renal function These data support the hypothesis that the development of 2K1C hypertension is an Ang II-dependent phenomenon inducing the contralateral kidney to increase local Ang II content. Augmented intrarenal Ang II, via intracellular sequestration or from a renin-independent positive amplification mechanism, along with an inappropriate renal functional response may participate as a sustained hypertensinogenic stimulus