RESUMEN
Previous studies have shown that chronic low-dose administration of 40 ng/min angiotensin II by osmotic minipump to uninephrectomized rats mimics the temporal hypertensive response and the circulating angiotensin II levels observed in two-kidney, one clip Goldblatt rats. Furthermore, renal tissue angiotensin II contents were higher than the circulating angiotensin II levels, suggesting that circulating angiotensin II induces endogenous intrarenal angiotensin II production. The present study examined the molecular mechanisms by which intrarenal angiotensin II production is modulated in angiotensin II-induced and two-kidney Goldblatt hypertension. Two weeks after clipping, intrarenal renin mRNA levels were elevated threefold in the clipped kidney of Goldblatt rats but were markedly suppressed in the nonclipped kidneys of Goldblatt rats (28% of control values) and in the remaining kidney of uninephrectomized angiotensin II-infused rats (7% of control values). In contrast, there were sustained levels of angiotensinogen mRNA in the kidneys and livers of Goldblatt and angiotensin II-infused rats, indicating differential regulation of the genes of the renin-angiotensin system. Renal kallikrein gene expression was not altered in either of the hypertensive groups 14 days after the induction of hypertension, suggesting the absence of an enhanced counteracting kinin influence.
Asunto(s)
Angiotensina II/biosíntesis , Angiotensinógeno/biosíntesis , Regulación de la Expresión Génica , Hipertensión Renovascular/metabolismo , Calicreínas/biosíntesis , Riñón/enzimología , Sistema Renina-Angiotensina , Renina/biosíntesis , Angiotensina II/sangre , Animales , Presión Sanguínea , Northern Blotting , Hipertensión Renovascular/fisiopatología , Masculino , ARN/aislamiento & purificación , ARN/metabolismo , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Renina/sangreRESUMEN
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.
Asunto(s)
Angiotensina II/farmacología , Riñón/efectos de los fármacos , Receptores de Angiotensina/fisiología , Angiotensina II/farmacocinética , Angiotensinógeno/análisis , Animales , Compuestos de Bifenilo/farmacología , Hipertensión/inducido químicamente , Imidazoles/farmacología , Losartán , Masculino , Ratas , Ratas Sprague-Dawley , Renina/sangre , Tetrazoles/farmacologíaRESUMEN
The objective of this study was to investigate the singular role of elevated angiotensin II (ANG II) levels in the development of two-kidney, one-clip (2K1C) Goldblatt hypertension in the rat and specifically in the altered intrarenal ANG II levels that occur in the nonclipped kidney. As a substitute for the clipped kidney, chronic delivery of ANG II (40 ng/min) via an osmotic minipump implanted subcutaneously was used to mimic plasma ANG II levels observed in 2K1C rats during the developmental phase of hypertension. Arterial pressure increased gradually over a period of 14 days, and a pressure profile similar in magnitude and temporal pattern to that of the 2K1C rats was observed. Systemic ANG II was elevated to similar levels in the 2K1C (60 +/- 13 fmol/ml) and ANG II-infused rats (72 +/- 15 fmol/ml) compared with intact two-kidney control animals (31 +/- 6 fmol/ml; P < 0.05) or uninephrectomized rats (13 +/- 1 fmol/ml; P < 0.05). Although renin content was markedly suppressed (80%), intrarenal ANG II content of the contralateral kidneys of the 2K1C groups (86 +/- 12 fmol/g) and the ANG II-infused group (150 +/- 17 fmol/g) was greater than that of the two-kidney control (53 +/- 7 fmol/g; P < 0.05) and uninephrectomized control animals (42 +/- 5 fmol/g; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Angiotensina II/metabolismo , Angiotensina II/farmacología , Riñón/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Diuresis/efectos de los fármacos , Tasa de Filtración Glomerular , Hemodinámica/efectos de los fármacos , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/fisiopatología , Bombas de Infusión , Masculino , Peptidil-Dipeptidasa A/metabolismo , Ratas , Ratas Sprague-Dawley , Circulación Renal , Sistema Renina-Angiotensina , Factores de TiempoRESUMEN
Previous studies have indicated that the hypertension that develops after unilateral arterial constriction (2 kidney, 1 clip) involves an active participation by the non-clipped contralateral kidney. Even though the non-clipped kidney is not the initial causative factors, and despite the progressive renin depletion during the early weeks following clipping, the non-clipped kidney is highly responsive to angiotensin blockers. Furthermore, the non-clipped kidney has augmented tissue ANG II levels and ACE activity suggesting that some renin-independent mechanism may be stimulating intrarenal ANG II formation. This model has been simulated by infusing ANG II at low subpressor doses (40 ng/min) to uninephrectomized rats for 14 days. With this model, plasma and renal renin levels are markedly suppressed; however, the renal ANG II levels are increased to levels above those that can be explained on the basis of circulating ANG II. In agreement with the responses observed in the non-clipped kidney of 2K1C rats, there is also an increased renal ACE activity. In contrast to the marked suppression of renin gene expression and renin activity, angiotensinogen gene expression is not suppressed. These results support the hypothesis that small elevations in circulating ANG II stimulate intrarenal ANG II production through a renin-independent mechanism.