Endoplasmic Reticulum (ER) Stress in Part Mediates Effects of Angiotensin II in Pancreatic Beta Cells

Latha Ramalingam, Boontharick Sopontammarak, Kalhara R Menikdiwela, Naima Moustaid-Moussa

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Introduction: The renin angiotensin aldosterone system (RAAS) is a hormone system known for its role in regulating blood pressure and fluid balance. Numerous RAAS inhibitors routinely prescribed for hypertension have also beneficial effects in type 2 diabetes (T2D) prevention. RAAS components are expressed locally in many tissues, including adipose tissue and pancreas, where they exert metabolic effects through RAAS bioactive hormone angiotensin II (Ang II). Pancreatic beta cells are specialized insulin-producing cells; they have also developed endoplasmic reticulum (ER), which contributes to beta cell dysfunction, when proteins are misfolded in disease states such as T2D. However, no studies have investigated the relationship between RAAS and ER stress in beta cells as a mechanism linking pancreatic RAAS to T2D. Hence, we hypothesized that Ang II treatment of beta cells increases ER stress and inflammation leading to reduced insulin secretion.

Methods: To test this hypothesis, we treated clonal INS-1E beta cells and human islets with Ang II and assessed changes in ER stress markers. INS-1E beta cells were also used for measuring insulin secretion and for assessing the effects of various RAAS and ER stress inhibitors.

Results: We demonstrated that Ang II significantly increased the expression of ER stress genes such as Chop and Atf4 and reduced insulin secretion. Furthermore, inhibition of Ang II production with an angiotensin converting enzyme inhibitor (ACEi, captopril) significantly reduced ER stress. Moreover, the Ang II receptor blockade reduced ER stress significantly and rescued insulin secretion.

Discussion: This research provides new mechanistic insight into the role of RAAS activation via ER stress on beta cell dysfunction and provides additional evidence for protective effects of RAAS inhibition in T2D.

Original languageEnglish (US)
Pages (from-to)2843-2853
Number of pages11
JournalDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy
Volume13
DOIs
StatePublished - Aug 26 2020
Externally publishedYes

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