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

PLoS One. 2019 Sep 3;14(9):e0222005. doi: 10.1371/journal.pone.0222005. eCollection 2019.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldosterone / metabolism*
  • Angiotensin II / metabolism*
  • Animals
  • Calcium Signaling
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Osmoregulation / genetics
  • Osmoregulation / physiology
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Protein Structure, Quaternary
  • Receptor, Angiotensin, Type 1 / chemistry
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Gastrointestinal Hormone / chemistry
  • Receptors, Gastrointestinal Hormone / deficiency
  • Receptors, Gastrointestinal Hormone / metabolism*
  • Zona Glomerulosa / cytology
  • Zona Glomerulosa / metabolism

Substances

  • Peptide Fragments
  • Receptor, Angiotensin, Type 1
  • Receptors, G-Protein-Coupled
  • Receptors, Gastrointestinal Hormone
  • secretin receptor
  • Angiotensin II
  • Aldosterone

Grants and funding

This work was supported by HK government RGC Grant GRF 764510M, 765011M, 764812M, 765113M, 17112014 and CRF grant HKU6/CRF/11G to Billy K.C. Chow. The authors extend their appreciation to the International Scientific Partnership Program ISPP at King Saud University for funding this research work through ISPP# 008.