Abstract 440: Activation of the Brain Renin-angiotensin System is Critically Involved in the Hypertension Associated With Bbs

Abstract

Bardet-Biedl syndrome (BBS) is a human autosomal recessive disorder characterized by a pleiotropic of phenotypes including obesity, renal abnormalities, mental retardation, retinal pigmentary dystrophy, polydactyly and hypogenitalism. Hypertension is also common in BBS patients, except BBS2. Consistent with this, we previously demonstrated that obese Bbs2 knockout mice are normotensive while obese Bbs4 null mice are hypertensive. However, the underlying molecular mechanisms of hypertension in BBS remain poorly defined. Using BBS mice, we tested whether abnormalities in the brain renin-angiotensin system (RAS) may contribute to the increased arterial pressure in BBS. Using real time PCR, we found that mRNA expression of RAS components were differentially altered in Bbs2 -/- and Bbs4 -/- mice. Compared to wild type controls, the hypertensive Bbs4 -/- mice exhibited significantly (P<0.05) elevated expression of renin (160%), angiotensin converting enzyme (ACE, 185%), angiotensin type 1a receptor (AT1aR, 143%) and AT1bR (244%) in the brain. Notably, while the expression of ACE was increased (154%) in the brain of the normotensive Bbs2 -/- mice, the expression of renin, AT1aR and AT1bR were significantly (P<0.05) decreased by 56%, 60% and 36%, respectively, relative to controls. Next, we examined the functional consequences of the elevated brain RAS components in Bbs4 -/- mice. Consistent with our previous findings, radiotelemetric mean arterial pressure was significantly (P<0.05) elevated in the obese Bbs4 -/- mice (114±3 mmHg) relative to wild type controls (101±1 mmHg). Moreover, Bbs4 -/- mice exhibited an exaggerated decrease in arterial pressure in response to intracerebroventricular (ICV) administration of losartan (AT1 receptor antagonist). Indeed, ICV losartan (10 g) decreased mean arterial pressure by 24±7 mmHg in Bbs4 -/- mice vs. 5±10 mmHg in wild type controls (P<0.05). Our data indicate that overactivity of the brain RAS may account for the high blood pressure associated with BBS. This study provides a novel molecular mechanism for the hypertension associated with BBS.