Abstract 098: Susceptibility of Mice Lacking Renin-B to Chronic Angiotensin II Infusion

Abstract

Prior experience to various hypertensive conditions enhances the response to subsequent hypertensive challenges and the activation of the brain renin angiotensin system (RAS) is required for the sensitization to these hypertensive challenges. We previously showed that the brain-specific renin alternative isoform (Ren-b) tonically inhibits the activation of the brain RAS and that ablation of Ren-b (Ren-b KO) results in brain RAS disinhibition leading to elevated blood pressure (BP). Retrospective analysis of five cohorts of mice indicated that Ren-b KO model exhibits a high degree of variability in BP, which may be attributed to the susceptibility to stress. Therefore, we hypothesized that Ren-b KO are sensitized to hypertensive challenge such as angiotensin (Ang) II. Wildtype (WT) or Ren-b KO were infused with either vehicle or Ang II (400 ng/kg/min; sc.) via osmotic minipumps for 4 weeks. Ang II significantly increased BP in both WT and Ren-b KO to the same degree (WT+veh: 103±4 vs WT+Ang: 120±4 mmHg; p = 0.01 (n=10-12) and KO+veh: 104±3 vs KO+Ang: 118±5 mmHg; p = 0.03 (n=10-14)). Although the BP between Ren-b KO and WT mice was elevated equally, Ang II induced an exaggerated suppression of plasma renin in Ren-b KO compared to WT (WT+Ang: 14.8±2.1 vs KO±Ang: 7.2±2.6 ng/ml; p = 0. 03; n=7-9). Ren-b KO exhibited enhanced Ang II-induced dipsogenic response (WT+Ang: 3.7±0.3 vs KO+Ang: 4.6±0.4 ml/day; p = 0. 05; n=10-12) and elevated heart weight (WT+Ang: 4.8±0.2 vs KO±Ang: 5.2±0.1 mg/g of body weight; p = 0.03; n=10-12) concomitant with an increased cardiac collagen type I alpha-2 mRNA expression (p = 0.03; n=7-9). Altogether, this data indicates that in the presence of Ang II, Ren-b KO exhibits higher susceptibility to cardiovascular disease. After successive breeding and backcrossing Ren-b KO developed a milder and more varied baseline BP elevation compared to our initial cohorts. This suggests that epigenetic silencing or other physiological and molecular mechanisms might compensate for some of the cardiovascular alterations driven by the genetic deletion of renin-b. Studies of a conditional Ren-b KO model will be used to elucidate the physiological and/or pathophysiological consequences of an acute downregulation of renin-b in adulthood.