1. Academic Validation
  2. Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)

Neprilysin Is Required for Angiotensin-(1-7)'s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1-2)

  • Diabetes. 2017 Aug;66(8):2201-2212. doi: 10.2337/db16-1318.
Gurkirat S Brar 1 Breanne M Barrow 1 Matthew Watson 2 Ryan Griesbach 3 Edwina Choung 1 Andrew Welch 3 Bela Ruzsicska 4 Daniel P Raleigh 2 Sakeneh Zraika 5 3
Affiliations

Affiliations

  • 1 Veterans Affairs Puget Sound Health Care System, Seattle, WA.
  • 2 Department of Chemistry, Stony Brook University, Stony Brook, NY.
  • 3 Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA.
  • 4 Institute for Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY.
  • 5 Veterans Affairs Puget Sound Health Care System, Seattle, WA zraikas@uw.edu.
Abstract

Recent work has renewed interest in therapies targeting the renin-angiotensin system (Ras) to improve β-cell function in type 2 diabetes. Studies show that generation of angiotensin-(1-7) by ACE2 and its binding to the Mas receptor (MasR) improves glucose homeostasis, partly by enhancing glucose-stimulated Insulin secretion (GSIS). Thus, islet ACE2 upregulation is viewed as a desirable therapeutic goal. Here, we show that, although endogenous islet ACE2 expression is sparse, its inhibition abrogates angiotensin-(1-7)-mediated GSIS. However, a more widely expressed islet peptidase, Neprilysin, degrades angiotensin-(1-7) into several Peptides. In neprilysin-deficient mouse islets, angiotensin-(1-7) and neprilysin-derived degradation products angiotensin-(1-4), angiotensin-(5-7), and angiotensin-(3-4) failed to enhance GSIS. Conversely, angiotensin-(1-2) enhanced GSIS in both neprilysin-deficient and wild-type islets. Rather than mediating this effect via activation of the G-protein-coupled receptor (GPCR) MasR, angiotensin-(1-2) was found to signal via another GPCR, namely GPCR family C group 6 member A (GPRC6A). In conclusion, in islets, intact angiotensin-(1-7) is not the primary mediator of beneficial effects ascribed to the ACE2/angiotensin-(1-7)/MasR axis. Our findings warrant caution for the concurrent use of angiotensin-(1-7) compounds and Neprilysin inhibitors as therapies for diabetes.

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