Mutations in Cullin-3 (CUL3) cause hypertension (HTN). We examined the role of smooth muscle cell (SMC) CUL3 in the regulation of renin gene expression. Mice with SMC-specific CUL3 deletion (S-CUL3-KO Show more
Mutations in Cullin-3 (CUL3) cause hypertension (HTN). We examined the role of smooth muscle cell (SMC) CUL3 in the regulation of renin gene expression. Mice with SMC-specific CUL3 deletion (S-CUL3-KO) developed severe HTN with paradoxically preserved levels of plasma angiotensin peptides and renal renin expression. Cre-recombinase was active in juxtaglomerular (JG) cells, resulting in decreased CUL3 expression. We evaluated components of the renin cell baroreceptor and revealed preserved Lamin A/C but decreased integrin β1 expression in S-CUL3-KO. We hypothesized that Rab proteins are involved in integrin β1 downregulation. Silencing either Rab21 or Rab5 in CUL3-deficient HEK293 cells increased integrin β1 protein. Coimmunoprecipitation revealed a direct interaction between Rab5 and CUL3. CUL3 deficiency increased Rab5, suggesting it is regulated by a CUL3-mediated mechanism and that CUL3 deficiency results in loss of Rab protein turnover, leading to enhanced integrin β1 internalization. We conclude that the loss of integrin β1 from JG cells impairs the mechanosensory function of the renin cell baroreceptor, which underlies the persistent renin expression observed in hypertensive S-CUL3-KO mice. These findings provide insights into the molecular mechanisms of HTN, revealing that dysregulation of Rab proteins and integrin β1 in the kidney due to CUL3 deficiency contributes to the development of HTN. Show less
The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothala Show more
The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC Show less