Angiotensin(1–7) activates MAS-1 and upregulates CFTR to promote insulin secretion in pancreatic β-cells: the association with type 2 diabetes

Xue Lian Zhang, Xinyi Zhao, Yong Wu, Wen Qing Huang, Jun Jiang Chen, Peijie Hu, Wei Liu, Yi Wen Chen, Jin Hao, Rong Rong Xie, Hsiao Chang Chan, Ye Chun Ruan, Hui Chen, Jinghui Guo

Research output: Journal article publicationJournal articleAcademic researchpeer-review

Abstract

Objective: The beneficial effect of angiotensin(1–7) (Ang(1–7)), via the activation of its receptor, MAS-1, has been noted in diabetes treatment; however, how Ang(1–7) or MAS-1 affects insulin secretion remains elusive and whether the endogenous level of Ang(1–7) or MAS-1 is altered in diabetic individuals remains unexplored. We recently identified an important role of cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated Cl channel, in the regulation of insulin secretion. Here, we tested the possible involvement of CFTR in mediating Ang(1–7)’s effect on insulin secretion and measured the level of Ang(1–7), MAS-1 as well as CFTR in the blood of individuals with or without type 2 diabetes. Methods: Ang(1–7)/MAS-1/CFTR pathway was determined by specific inhibitors, gene manipulation, Western blotting as well as insulin ELISA in a pancreatic β-cell line, RINm5F. Human blood samples were collected from 333 individuals with (n = 197) and without (n = 136) type 2 diabetes. Ang(1–7), MAS-1 and CFTR levels in the human blood were determined by ELISA. Results: In RINm5F cells, Ang(1–7) induced intracellular cAMP increase, cAMP-response element binding protein (CREB) activation, enhanced CFTR expression and potentiated glucose-stimulated insulin secretion, which were abolished by a selective CFTR inhibitor, RNAi-knockdown of CFTR, or inhibition of MAS-1. In human subjects, the blood levels of MAS-1 and CFTR, but not Ang(1–7), were significantly higher in individuals with type 2 diabetes as compared to those in non-diabetic healthy subjects. In addition, blood levels of MAS-1 and CFTR were in significant positive correlation in type-2 diabetic but not non-diabetic subjects. Conclusion: These results suggested that MAS-1 and CFTR as key players in mediating Ang(1–7)-promoted insulin secretion in pancreatic β-cells; MAS-1 and CFTR are positively correlated and both upregulated in type 2 diabetes.

Original languageEnglish
Article numbere210357
JournalEndocrine Connections
Volume11
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022

Keywords

  • Angiotensin(1-7)
  • CFTR
  • Insulin
  • MAS-1
  • p-CREB
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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