Abstract 623: Upregulation of Renin-Angiotensin System and Inflammatory Mechanisms in the Prenatally Programmed Hypertension

Abstract

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.