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

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.

The Interplay of Mitochondrial Oxidative Stress and Endoplasmic Reticulum Stress in Cardiovascular Fibrosis in Obese Rats

“…Importantly, cardiac and vascular cells exposed to Ang II presented ER stress activation characterized by an upregulation of ER stress markers. This effect was previously observed in adipocytes [ 66 ], in podocytes [ 67 ] and in pancreatic β cells [ 68 ]. We show for the first time that Ang II promotes ER stress activation in cardiac fibroblasts and VSMCs through mitochondrial oxidative stress production.…”

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

“…With some exceptions [ 301 , 302 , 303 , 304 ], several studies have shown the detrimental role of AGT-derived AngII on insulin release in vitro, ex vivo, and in vivo, both in animals and humans, which is at least partially mediated by reductions in proinsulin biosynthesis [ 305 , 306 , 307 , 308 , 309 , 310 , 311 , 312 ]. Concordantly, the inhibition of the RAS system has been demonstrated to be responsible for increased insulin biosynthesis and release in several obese, prediabetic, or diabetic models [ 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 321 ].…”

Interactions between diabetes and COVID-19: A narrative review

“…Similarly, in a genetic murine model of obesity and diabetes, ACE2 overexpression in pancreas, improved glycemic control through Ang-(1-7), inducing both β-cell proliferation and apoptosis reduction[ 102 ]. As expected, similarly as a loss of ACE2, Ang II supplementation in beta cells significantly increased endoplasmic reticulum (ER) stress and inflammation leading to reduced insulin secretion whereas Ang II receptor blockade in beta cells reduced significantly ER stress and rescues insulin secretion[ 119 ].…”