Proximal Tubular Angiotensin II Levels and Renal Functional Responses to AT ₁ Receptor Blockade in Nonclipped Kidneys of Goldblatt Hypertensive Rats

Abstract

Abstract-Previous studies have shown that whereas the nonclipped kidney in two-kidney, one clip (2K1C) rats undergoes marked depletion of renin content and renin mRNA, intrarenal angiotensin II (Ang II) levels are not suppressed; however, the distribution and functional consequences of intrarenal Ang II remain unclear. The present study was performed to assess the plasma, kidney, and proximal tubular fluid levels of Ang II and the renal responses to intrarenal Ang II blockade in the nonclipped kidneys of rats clipped for 3 weeks. The Ang II concentrations in proximal tubular fluid averaged 9.19Ϯ1.06 pmol/mL, whereas plasma Ang II levels averaged 483Ϯ55 fmol/mL and kidney Ang II content averaged 650Ϯ66 fmol/g. Thus, as found in kidneys from normal rats with normal renin levels, proximal tubular fluid concentrations of Ang II are in the nanomolar range. To avoid the confounding effects of decreases in mean arterial pressure (MAP), we administered the nonsurmountable AT 1 receptor antagonist candesartan directly into the renal artery of nonclipped kidneys (nϭ10). The dose of candesartan (0.5 g) did not significantly decrease MAP in 2K1C rats (152Ϯ3 versus 148Ϯ3 mm Hg), but effectively prevented the renal vasoconstriction elicited by an intra-arterial bolus of Ang II (2 ng). Candesartan elicited significant increases in glomerular filtration rate (GFR) (0.65Ϯ0.06 to 0.83Ϯ0.11 mL ⅐ min Ϫ1 ⅐ g Ϫ1) and renal blood flow (6.3Ϯ0.7 to 7.3Ϯ0.9 mL ⅐ min Ϫ1 ⅐ g Ϫ1 ), and proportionately greater increases in absolute sodium excretion (0.23Ϯ0.07 to 1.13Ϯ0.34 mol ⅐ min Ϫ1 ⅐ g Ϫ1 ) and fractional sodium excretion (0.38Ϯ0.1% to 1.22Ϯ0.35%) in 2K1C hypertensive rats. These results show that proximal tubular fluid concentrations of Ang II are in the nanomolar range and are much higher than can be explained on the basis of plasma levels. Further, the data show that the intratubular levels of Ang II in the nonclipped kidneys of 2K1C rats remain at levels found in kidneys with normal renin content and could be exerting effects to suppress renal hemodynamic and glomerular function and to enhance tubular reabsorption rate. (Hypertension. 1999;33:102-107.) Key Words: renin-angiotensin system Ⅲ hypertension, renal Ⅲ angiotensin antagonist Ⅲ receptors, angiotensin Ⅲ glomerular filtration rate Ⅲ renal blood flow P revious studies have shown the pivotal role of the renin-angiotensin system (RAS) in the development and maintenance of two-kidney, one clip (2K1C) hypertension.

Collecting Duct Renin Is Upregulated in Both Kidneys of 2-Kidney, 1-Clip Goldblatt Hypertensive Rats

“…4 Accordingly, the initial event caused by unilateral renal artery clipping may initiate the cascade responsible for intrarenal Ang II augmentation in the NCK. 14,24 Furthermore, it is also unlikely that circulating renin or prorenin is the stimulus for the upregulation of renin in the CD cells, because chronic Ang II-infused rats exhibit stimulation of renin in distal nephron segments in a setting of marked suppression of PRA. 8 The results suggest that the local amplification mechanism of intrarenal Ang II on distal nephron renin may allow a moderate increase in Ang II to further augment the intratubular and interstitial Ang II levels to achieve rapid homeostatic regulation of sodium balance as needed in a setting of volume depletion.…”

Angiotensinase activities in the kidney of renovascular hypertensive rats

“…In this model of hypertension, the non-clipped kidney is renin depleted but the intrarenal Ang II levels are not suppressed and Ang II concentrations in proximal tubular fluid remain high [20]. This could stimulate proximal tubular reabsorption rate, which may contribute to the development and maintenance of hypertension by maintaining an inappropriately high sodium reabsorption rate even at elevated arterial pressure [4]. Clipped and non-clipped kidneys show a slight reduction of aminopeptidase A (glutamyl-aminopeptidase, GluAP, Ang II-degrading enzyme) expression in cortical homogenates of G2K1C animals.…”

Intrarenal Angiotensin II Augmentation in Angiotensin II Dependent Hypertension.

“…Micropuncture experiments have shown that proximal tubular fluid contains very high concentrations of the ANG peptides and angiotensinogen (54)(55)(56). Indeed, both proximal tubule ANG I and ANG II concentrations have been shown to be in the range of 3-10 pmol/ml which are from 10 to 100 times higher than the corresponding plasma ANG I and ANG II concentra- Similarly high concentrations of ANG II have been found in proximal tubular fluid from the non-clipped kidneys of 2K1C Goldblatt hypertensive rats and in TGR (Ren 2) rats (47,53). In both cases, the kidneys were renin depleted and exposed to elevated systemic arterial pressures.…”

“…This responsiveness of the non-clipped kidney to blockade of the reninangiotensin system persists even during the maintenance phase of hypertension when the plasma renin and ANG II concentrations have returned to near normal levels (36,38). The continued influence of ANG II on the non-clipped kidney after circulating levels return towards normal is of critical importance to the hypertensinogenic process (31,33,37,47,49,50).…”

“…However, functional data have demonstrated that the non-clipped kidney is still highly responsive to pharmacological blockade of the renin-angiotensin system with ACE inhibitors or ANG II receptor antagonists (29,31,33,45,46). The non-clipped kidney responds to acute ANG II receptor blockade by increasing sodium excretion, RBF and GFR (33,47).…”