Susceptibility of Mice Lacking Renin‐b to Chronic Angiotensin II Infusion

In addition to the classical endocrine renin angiotensin system (RAS), local activity of the RAS has been detected in many tissues including the brain. The brain renin angiotensin system is known for its importance in blood pressure regulation and water homeostasis. The brain specific isoform of renin, termed renin‐b, has been proposed as a negative regulator of the brain renin‐angiotensin system (RAS) since the selective ablation of ren‐b (Ren‐b KO) in mice results in brain RAS disinhibition leading to blood pressure (BP) elevation. New cohorts of Ren‐b KO mice, however, do not exhibit elevated BP and the retrospective analysis of five previous cohorts indicated that Ren‐b KO model exhibits a high degree of variability in BP, which may be attributed to the susceptibility to different stressors. Importantly, Ren‐b KO (including recent cohorts) exhibit suppressed plasma renin and angiotensin II (Ang II) implying that suppression of the endocrine RAS might compensate for the elevation of the brain RAS activity in those Ren‐b KO mice exhibiting normal BP. Therefore, we hypothesized that Ren‐b KO are sensitized to exogenous systemic infusion of 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, 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 exhibited a trend toward increase in levels of urinary aldosterone (WT+Ang: 14.6±1.4 vs KO+Ang: 17.8±1.7 mmHg) and copeptin, a marker of arginine vasopressin (WT+Ang: 11.5±2.6 vs KO+Ang: 22.2±5.2 mmHg). BP, drinking, aldosterone, and copeptin data in Ang II‐treated Ren‐b KO exhibits a bi‐modal distribution indicating that some mice are, whereas others, are not sensitized to Ang II. Ang II‐treated Ren‐b KO exhibited 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) and trend toward increase in tumor necrosis factor‐α. 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). However, there was no difference in the renin mRNA and protein levels of renin in the renal cortex. We used in situ hybridization technique to localize renin expression in the renin cortex. We did not observe a shift from glomerular to tubular renin expression in Ren‐b KO. We conclude Ren‐b KO exhibits higher sensitivity to Ang II‐induced aldosterone secretion and drinking responses as well as elevated susceptibility to Ang II‐evoked cardiac remodeling. The mechanism causing suppressed plasma renin in Ren‐b KO remains unclear. Studies of a conditional Ren‐b KO model will be used to elucidate the physiological consequences of downregulating renin‐b in specific neuroanatomical regions. Support or Funding Information P01 HL084207 to Sigmund and 5T32HL134643 to Nakagawa