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Endocrine

pp 1–11 | Cite as

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

  • Hong Weng Pang
  • Andrea Linares
  • Leena Couling
  • Jessica Santollo
  • Leonardo Ancheta
  • Derek Daniels
  • Robert C. SpethEmail author
Original Article

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 Biased agonism Bovine serum albumin-conjugated angiotensin II Calcium mobilization Aldosterone release Salt appetite 

Abbreviations

Ang II

angiotensin II;

ARBs

angiotensin receptor blockers;

AT1R

angiotensin II receptor subtype 1;

AT2R

angiotensin II receptor subtype 2;

BSA-Ang II

Ang II conjugated to bovine albumin;

G-protein

guanine nucleotide binding protein;

GPCR

G-protein-coupled receptors;

ICV

intracerebroventricular;

MAPK

mitogen-activated protein kinase;

SI Ang II

Sarcosine1 Isoleucine8 angiotensin II;

SII Ang II

Sarcosine1 Isoleucine4 Isoleucine8 angiotensin II;

SMCC

succinimydyl 4-[N-maleimidomethyl1]cyclohexane-1-carboxylate.

Notes

Acknowledgements

The authors thank Dr. Anastasios Lymperopoulos for assistance in experimental design and Dr. Douglas Lappi and Denise Higgins for editorial suggestions. This study was funded by a President’s Faculty Research Development Grant from Nova Southeastern University and the Cardiovascular Neuroscience Fund, Nova Southeastern University and NIH, HL-113905.

Author contributions

Participated in research design: H.W.P., A.L., L.C., J.S., D.D., and R.C.S.; Conducted experiments and performed data analysis: H.W.P., A.L., L.C., J.S., L.A., D.D., and R.C.S.; Wrote or contributed to the writing of the manuscript: H.W.P., J.S., L.A., D.D., and R.C.S.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.College of PharmacyNova Southeastern UniversityFt. LauderdaleUSA
  2. 2.Behavioral Neuroscience Program, Department of Psychology, University at BuffaloState University of New YorkBuffaloUSA
  3. 3.Department of BiologyUniversity of KentuckyLexingtonUSA
  4. 4.Advanced Targeting SystemsSan DiegoUSA
  5. 5.Center for Ingestive Behavior Research, University at BuffaloState University of New YorkBuffaloUSA
  6. 6.Department of Pharmacology and Physiology, College of MedicineGeorgetown UniversityWashingtonUSA

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