Novel high molecular weight albumin-conjugated angiotensin II activates β-arrestin and G-protein pathways

Endocrine. 2019 Nov;66(2):349-359. doi: 10.1007/s12020-019-01930-z. Epub 2019 Apr 24.

Abstract

Purpose: To study the ability of a novel bovine serum albumin-angiotensin II (BSA-Ang II) conjugate to effect responses of the AT1 angiotensin II receptor subtype mediated by the G-protein-coupled and the beta-arrestin pathways.

Methods: Angiotensin II (Ang II) was conjugated with bovine serum albumin and compared with Ang II for competition binding to AT1 receptors, to stimulate aldosterone release from adrenocortical cells, to promote beta-arrestin binding to AT1 receptors, to promote calcium mobilization, and stimulate drinking of water and saline by rats.

Results: The BSA-Ang II conjugate was less potent competing for AT1R binding, but was equally efficacious at stimulating aldosterone release from H295R adrenocortical cells. Both BSA-Ang II and Ang II stimulated calcium mobilization and beta-arrestin binding to AT1 receptors. BSA-Ang II and Ang II stimulated water appetite equivalently but BSA-Ang II stimulated saline appetite more than Ang II. Both BSA-Ang II and Ang II were considerably more potent at causing calcium mobilization than β-arrestin binding.

Conclusions: Addition of a high molecular weight molecule to Ang II reduced its AT1 receptor binding affinity, but did not significantly alter stimulation of aldosterone release or water consumption. The BSA-Ang II conjugate caused a greater saline appetite than Ang II suggesting that it may be a more efficacious agonist of this beta-arrestin-mediated response than Ang II. The higher potency calcium signaling response suggests that the G-protein-coupled responses predominate at physiological concentrations of Ang II, while the beta-arrestin response requires pathophysiological or pharmacological concentrations of Ang II to occur.

Keywords: AT1 receptor; Aldosterone release; Biased agonism; Bovine serum albumin-conjugated angiotensin II; Calcium mobilization; Salt appetite.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex / drug effects*
  • Adrenal Cortex / metabolism
  • Aldosterone / metabolism
  • Angiotensin II / pharmacology*
  • Animals
  • Calcium Signaling / drug effects
  • Cell Line, Tumor
  • Drinking / drug effects
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1 / metabolism
  • Serum Albumin, Bovine / pharmacology*
  • Signal Transduction / drug effects*
  • beta-Arrestins / metabolism*

Substances

  • Receptor, Angiotensin, Type 1
  • beta-Arrestins
  • Angiotensin II
  • Serum Albumin, Bovine
  • Aldosterone