Functional Consequences of Calcium-Sensing Receptor (CaSR) Gene- Knockdown in Renin-Secreting Cells in Mice - conference presentation

Background: Renin-secreting cells express the CaSR, but its function is unclear. Methods: Utilizing the cre/lox system, we generated a CaSR mutant mouse model with knockdown of the CaSR in cells expressing renin (reninCre/+/CaSRloxlox), and compared with control mice (CaSRloxlox). Results: On normal diet (0.8% NaCl) or after 6 days of low-salt diet (0.01% NaCl), systolic blood pressure (SBP, tailcuff in awake mice), heart rate (HR) and plasma renin concentration (PRC) were not different between genotypes. In contrast, 6 days of high-salt diet (4.0% NaCl) increased SBP in CaSR mutants relative to the change observed in controls (∆ mmHg: 3±2 vs -7±2, n=6-9, P<0.05). HR was reduced over the first 48h (-45±2 bpm) only in CaSR mutants, potentially due to a compensatory baroreceptor response. PRC was similar in both genotypes despite lower renal renin mRNA expression in CaSR mutants vs controls (low-salt: 0.95±0.04 vs 1.46±0.19; high-salt: 0.31±0.05 vs 0.60±0.10; P<0.05 each). Considering the strong correlation between renal mRNA and protein expression of renin, this may indicate a “fractional” increase in renin secretion in CaSR mutants. Acute i.p. injections of isoproterenol or furosemide increased PRC to a similar extent in both genotypes, but the effect of the ACE inhibitor, enalapril, on PRC was greater in CaSR mutants (∆ ng angiotensin I/ml per hr: 4471±474 vs 3056±118 in controls, n=5-6, P<0.05). Conclusions: We propose that enalapril unmasked an enhanced angiotensin II tone in CaSR mutants that feeds back to lower PRC (by reducing renin expression and/or secretion) when the inhibitory influence of the CaSR on renin secretion is reduced. The efficiency of this feedback may make it difficult to detect differences in PRC in the steady state. An inhibitory influence of the CaSR on renin secretion may facilitate NaCl homeostasis and maintain blood pressure in response to a high NaCl diet.