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Bouley R, Palomino Z, Tang S-S, Nunes P, Kobori H, Lu HA, Shum WW, Sabolic I, Brown D, Ingelfinger JR, Jung FF. Angiotensin II and hypertonicity modulate proximal tubular aquaporin 1 expression. Am J Physiol Renal Physiol 297: F1575-F1586, 2009. First published September 23, 2009; doi: 10.1152/ajprenal.90762.2008.--Aquaporin 1 (AQP1) is the major water channel in the renal proximal tubule (PT) and thin descending limb of Henle, but its regulation remains elusive. Here, we investigated the effect of ANG II, a key mediator of body water homeostasis, on AQP1 expression in immortalized rat proximal tubule cells (IRPTC) and rat kidney. Real-time PCR on IRPTC exposed to ANG II for 12 h revealed a biphasic effect AQP1 mRNA increased dose dependently in response to [10.sup.-12] to [10.sup.-8] M ANG II but decreased by 50% with [10.sup.-7] M ANG II. The twofold increase of AQP1 mRNA in the presence of [10.sup.-8] M ANG II was abolished by the AT1 receptor blocker losartan. Hypertonicity due to either NaCl or mannitol also upregulated AQP1 mRNA by threeand twofold, respectively. Immunocytochemistry and Western blotting revealed a two- to threefold increase in AQP1 protein expression in IRPTC exposed concomitantly to ANG II ([10.sup.-8]M) and hypertonic medium (either NaCl or mannitol), indicating that these stimuli were not additive. Three-dimensional reconstruction of confocal images suggested that AQP1 expression was increased by ANG II in both the apical and basolateral poles of IRPTC. In vivo studies showed that short-term ANG II infusion had a diuretic effect, while this effect was attenuated after several days of ANG II infusion. After 10 days, we observed a twofold increase in AQPI expression in the PT and thin descending limb of Henle of ANG II-infused rats that was abolished when rats were treated with the selective [AT.sub.1]-receptor antagonist olmesartan. Thus ANG II increases AQP1 expression in vitro and in vivo via direct interaction with the [AT.sub.1] receptor, providing an important regulatory mechanism to link PT water reabsorption to body fluid homeostasis via the renin-angiotensin system. renin angiotensin system; proximal tubule doi: 10.1152/ajprenal.90762.2008

Pathogenesis of hemodynamic abnormalities in the initial stages of diabetes reveals the occurrence of renin-angiotensin system. Blood pressure in the normotensive model is reduced by chronic angiotensin II (ANG II) receptor antagonism. Glomerular capillary pressure and efferent arteriolar resistance are attenuated by acute and chronic losartan therapy. The action of the converting enzyme inhibitor therapy reveals the restriction of ANG II production and action as a prominent function.

Strong evidence shows that renin-angiotensin system (RAS) is affected by adverse maternal nutrition during pregnancy. Early treatment of offspring with RAS inhibitors is able to prevent the development of prenatally programmed hypertension. The aim of this study was to evaluate renal RAS activity and inflammatory mechanisms and the effects of RAS inhibition in prenatally programmed hypertension. Sprague-Dawley rats were fed with standard diet (control group) or low protein (LP) diet during the period of pregnancy. After birth, dams were switched back to standard rat chow. After weaning, LP pups were randomized to either no treatment or to treatment with losartan. LP offspring presented lower birth weight when compared to CT group (5.3 ± 0.1 vs 6.4 ± 0.2 g, respectively, p<0.05). At 20 weeks of life, blood pressure levels were higher in the untreated LP group when compared to CT group (128.5 ± 0.9 vs 109.2 ± 1.9 mmHg, respectively, p<0.05). We also observed adverse histological features in the kidney of untreated LP animals when compared to CT group, including augmentation of relative interstitial area (9.27 ± 0.32 vs 3.86 ± 0.27 %, respectively, p<0.05), collagen concentration (3.53 ± 0.87 vs 0.68 ± 0.19%, respectively, p<0.05) and number of PCNA positive cells (7.36 ± 1.82 vs 1.95 ± 0.15 cells/0.274 mm2, respectively, p<0.05). Untreated LP group also had higher number of CD3 and CD68 positive cells in the kidney compared to CT group [CD3: 9.3 ± 0.5 vs 5.1 ± 0.3 cells/0.274 mm2 and CD68: 13.5 ± 1.0 vs 8.2 ± 0.9 cells/0.274 mm2, respectively, p<0.05), and higher levels of reactive oxygen species (3.6 ± 0.4 vs 1.7 ± 0.2 mmol/mg, respectively, p<0.05). In addition, renal levels of angiotensin II (Ang II) were higher in the untreated LP offspring compared to CT group (p<0.05), and inhibition of RAS was able to prevent renal injury and abolished infiltration of inflammatory cells, besides its hemodynamics benefits. The finding of high renal levels of Ang II associated with increased inflammatory infiltration and deleterious histological outcomes and the effectiveness of RAS inhibition in prevent them indicate that RAS, via Ang II/AT1 receptor, is responsible for initiating and perpetuating the inflammatory and fibrotic processes in the prenatally programmed kidney. [ABSTRACT FROM AUTHOR]