Neprilysin Is Required for Angiotensin-(1–7)’s Ability to Enhance Insulin Secretion via Its Proteolytic Activity to Generate Angiotensin-(1–2)
| Autor: | Andrew A. Welch, Breanne M. Barrow, Sakeneh Zraika, Bela P. Ruzsicska, Daniel P. Raleigh, Gurkirat S. Brar, Ryan Griesbach, Matthew D. Watson, Edwina Choung |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Angiotensins Endocrinology Diabetes and Metabolism medicine.medical_treatment GPRC6A Peptidyl-Dipeptidase A Biology Receptors G-Protein-Coupled Renin-Angiotensin System Mice 03 medical and health sciences Downregulation and upregulation Insulin-Secreting Cells Internal medicine Insulin Secretion Internal Medicine medicine Animals Insulin Glucose homeostasis Neprilysin geography geography.geographical_feature_category Pancreatic islets Islet Peptide Fragments Mice Inbred C57BL Glucose 030104 developmental biology Endocrinology medicine.anatomical_structure Islet Studies Proteolysis Angiotensin-Converting Enzyme 2 Angiotensin I Signal transduction hormones hormone substitutes and hormone antagonists Signal Transduction |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| DOI: | 10.2337/db16-1318 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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