The role of secretin and Its receptor in Angiotensin II-induced Aldosterone Biosynthesis and release

Secretin (SCT) and its receptor (SCTR) play an indispensable role in ANGII-induced water drinking behavior in central. Recently, we demonstrated that synthetic peptide homologous to the first transmembrane domain of angiotensin II (ANGII) receptor subtype 1a (AT1aR) inhibits SCTR/AT1aR heteromer formation in vitro and suppresses hyperosmotic shock-induced water drinking behavior when injected into the mouse lateral ventricle in vivo. Although ANGII is known to increase aldosterone release and biosynthesis, it remains unknown whether SCT and SCTR are involved. Here, C57BL/6N (WT) and SCTR knockout (SCTR-/-) mice were fed with either standard (0.3 % Na+) or low Na+ (0.03 % Na+) chow for 20 days. The protein levels of ANGII, SCT and aldosterone were determined by enzyme-linked immunosorbent assay (ELISA). Sodium restriction significantly increased plasma ANGII and aldosterone in WT mice. However, only ANGII was elevated in the SCTR-/-. Concomitantly, the plasma SCT was increased in WT but not in the SCTR-/-. Under low sodium diet, the zona glomerulosa (ZG) layer was only enlarged in WT adrenal gland. The mRNA and protein level of aldosterone synthase (CYP11B2) was also significantly increased in the WT exposed to low Na+ diet but not in the SCTR-/-. Although the plasma cholesterol level between WT and SCTR-/- was not different, the mRNA high-density-lipoprotein (HDL) cholesterol receptor (scavenger receptor BI) was increased only in the WT mice following sodium restriction. Furthermore, the accumulation of cholesterol, the precursor of aldosterone, was impaired in the adrenal gland obtained from SCTR-/- mice fed with low Na+ chow. Acute exposure to SCT (20 min) alone did not affect plasma aldosterone. However, in mice co-injected with SCT and ANGII, the plasma aldosterone was higher than in ANGII-injected mice. ANGII-induced increase in plasma aldosterone and CYP11B2 expression was also absence in the SCTR-/- mice. Taken together, the SCT-SCTR axis is required for ANGII-induced aldosterone release and biosynthesis by facilitating aldosterone precursor uptake and ZG hyperplasia/hypertrophy