Receptor-Mediated Intrarenal Angiotensin II Augmentation in Angiotensin II–Infused Rats

Abstract

Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increase intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126 +/- 2 mm Hg), systolic pressure in Ang II-infused rats exhibited a detectable increase by day 6 (146 +/- 2 mm Hg) and continued to increase to 189 +/- 5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II-infused rats for the duration of the infusion period (125 +/- 1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II-infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II-infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354 +/- 60 versus 164 +/- 23 fmol/g) in the Ang II-infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II-infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.

Intrarenal Angiotensin II Augmentation in Angiotensin II Dependent Hypertension.

“…The renal renin content and renin mRNA and the plasma renin activity are all markedly suppressed in this model (42). The critical new observation from these experiments was that renal ANG II content increased significantly after 8 to 10 days of ANG II infusion to levels substantially greater than could be explained by the circulating ANG II (52,63). These data support the presence of a positive amplification mechanism by which modest increases in circulating ANG II elicit more substantive increases in renal ANG II content.…”

“…These results uncovered important questions regarding the mechanisms responsible for the increases in intrarenal ANG II levels in the ANG II infused hypertensive rats. ANG II measurements in other tissues such as heart, aorta, and adrenal gland did not show disproportionate increases in ANG II levels so the changes observed seemed to be specific to the kidney (63). In addition, the increases in renal ANG II could not simply represent nonspecific accumulation because the levels expressed per gram of total kidney weight were much greater than the plasma concentrations.…”

“…Because plasma renin activity, renal renin content and renin mRNA levels are markedly suppressed, it can be concluded that the intrarenal ANG II amplification mechanism is not dependent on renin. While some of the intrarenal ANG II could be due to accumulation of circulating ANG II, there was also evidence for intrarenal formation of ANG II because both the renal angiotensinogen activity and kidney ANG I contents were not significantly reduced from control levels (63). In addition to the elevated intrarenal ANG II levels, it has also been shown that the renal AT1 receptor mRNA and protein levels are maintained in ANG II induced hypertension and do not show signs of downregulation (64).…”

“…To evaluate mechanisms responsible for the augmented intrarenal ANG II in renin depleted kidneys, further experiments were performed using a model of ANG II infused hypertension that leads to marked suppression of both circulating and tissue renin activity (42,52,62,63). Instead of renal arterial stenosis, an osmotic minipump containing ANG II was implanted.…”

“…Anderson and Peach (65) characterized the intracellular pathway of ANG II using an ANG II-colloidal gold conjugate and observed that the conjugate is internalized by AT1 receptors via small receptosomes and accumulates in large vesicles deep within the cell. It was suggested that not all of the internalized peptide was degraded by lysosomes and that part of the intracellularly delivered ANG II or an active metabolite could have unique intracellular functions Further experiments were performed by Zou et al (63) to determine if the intrarenal ANG II augmentation process required AT1 receptor activation as was shown for vascular smooth muscle cells. The AT1 receptor blocker, losartan, was given chronically to one group of ANG II infused rats.…”