Role of SCTR/AT1aR heteromer in mediating ANGII-induced aldosterone secretion.

Juan Bai,Billy K C Chow,Sarah O K Mak,Zhang Li,Ahmed Allam,Jamaan Ajarem,Karthi Duraisamy,Michael Bader

doi:10.1371/journal.pone.0222005

Abstract

The involvement of secretin (SCT) and its receptor (SCTR) in angiotensin II (ANGII)-mediated osmoregulation by forming SCTR/ angiotensin II type 1 receptor (AT1R) heteromer is well established. In this study, we demonstrated that SCTR/AT1R complex can mediate ANGII-induced aldosterone secretion/release through potentiating calcium mobilization. Through IHC and cAMP studies, we showed the presence of functional SCTR and AT1R in the primary zona glomerulosa (ZG) cells of C57BL/6N (C57), and functional AT1R and non-functional SCTR in SCTR knockout (SCTR-/-) mice. Calcium mobilization studies revealed the important role of SCTR on ANGII-mediated calcium mobilization in adrenal gland. The fluo4-AM loaded primary adrenal ZG cells from the C57 mice displayed a dose-dependent increase in intracellular calcium influx ([Ca2+]i) when exposed to ANGII but not from the SCTR-/- ZG cells. Synthetic SCTR transmembrane (TM) peptides STM-II/-IV were able to alter [Ca2+]i in C57 mice, but not the mice with mutated STM-II/-IV (STM-IIm/IVm) peptides. Through enzyme immunoassay (EIA), we measured the aldosterone release from primary ZG cells of both C57 and SCTR-/- mice by exposing them to ANGII (10nM). SCTR-/- ZG cells showed impaired ANGII-induced aldosterone secretion compared to the C57 mice. TM peptide, STM-II hindered the aldosterone secretion in ZG cells of C57 mice. These findings support the involvement of SCTR/AT1R heterodimer complex in aldosterone secretion/release through [Ca2+]i.

Highlights

Fluid homeostasis is a fundamental survival mechanism to all terrestrial mammals to defend continuous osmotic stress from the surroundings
By IHC staining, we showed the presence of SCTR in zona glomerulosa (ZG) cell layer of C57 mice, but not in ZG cell layer of SCTR-/mice (Fig 1A)
There is a significant reduction in the expression of AT2R mRNA in SCTR-/- ZG tissues when compared to C57 mice (Fig 1C)

Summary

Introduction

Fluid homeostasis is a fundamental survival mechanism to all terrestrial mammals to defend continuous osmotic stress from the surroundings. It helps the body to maintain fluid and electrolyte balance, sodium ions. Renin-angiotensin-aldosterone system (RAAS) is the major regulatory pathway within sodium homeostasis in which aldosterone production and release is mainly activated by angiotensin II (ANGII) release in adrenal cortex [1,2]. Aldosterone acts on kidney tubule cells and regulates ion channels to enhance sodium.

Methods

Results

Conclusion