High glucose increases extracellular matrix production in pancreatic stellate cells by activating the renin–angiotensin system

Abstract

Pancreatic stellate cells (PSCs) are involved in pancreatic inflammation and fibrosis. Recent studies have shown that blocking the renin-angiotensin system (RAS) attenuates pancreatic inflammation and fibrosis. However, there are few data about the direct effects of high glucose on extracellular matrix (ECM) protein synthesis and angiotensin II (Ang II) induction in PSCs. PSCs were isolated from male Sprague-Dawley rats and cultured in medium containing 5.5 mM (LG group) or 27 mM D-glucose (HG group). Levels of Ang II and transforming growth factor-beta (TGF-beta) in culture media were measured and Ang II-positive cells were counted. We used real-time polymerase chain reaction (PCR) to detect Ang II receptor expression and Western blot analysis for the expression of ECM proteins such as connective-tissue growth factor (CTGF) and collagen type IV. Cells were also treated with an Ang II-receptor antagonist (candesartan, 10 microM) or angiotensin-converting enzyme (ACE) inhibitor (ramiprilat, 100 nM). Thymidine uptake by PSCs increased fourfold with high glucose treatment. Ang II levels and the proportion of Ang II-positive PSCs were significantly increased after 6 h under high-glucose conditions. TGF-beta concentrations also increased significantly with high glucose. After 72 h, the expression of CTGF and collagen type IV proteins in high-glucose cultures increased significantly and this increase was effectively attenuated by the candesartan or the ramiprilat. All together, high glucose induced PSCs proliferation and ECM protein synthesis, and these effects were attenuated by an Ang II-receptor antagonist. The data suggest that pancreatic inflammation and fibrosis aggravated by hyperglycemia, and Ang II play an important role in this pathogenesis.

Palatinose and oleic acid act together to prevent pancreatic islet disruption in nondiabetic obese Zucker rats

“…In addition, in vitro studies showed that high concentration of glucose (which can result from sucrose feeding) induced pancreatic stellate cell (PSC) proliferation, resulting in increased extracellular matrix production and a consequent aggravation of fibrosis (37,38). High glucose and high insulin have been reported to have an additive effect on the activation and proliferation of rat PSCs (39).…”

Isolation and characterization of islet stellate cells in rat

“…22 The diabetic environment provides numerous signals which could lead to stellate cell activation. Thus, previous studies using classical PSCs have demonstrated that hyperglycemia, 16,31 activation of the RAS, 32 oxidative stress, 17,30 platelet-derived growth factors, 33 and inflammatory cytokines 34 all enhance PSC activation and proliferation. The environment of the diabetic islet is characterized by the presence of the hyperglycemia [35][36][37] and oxidative stress, [38][39][40] as well as macrophage infiltration and increased expression of inflammatory molecules such as IL-1, IL-6, TNF-α, MCP-1, and MIP-1α.…”

The Expanding Role of Oxidative Stress, Renin Angiotensin System, and β-Cell Dysfunction in the Cardiometabolic Syndrome and Type 2 Diabetes Mellitus

“…Hyperglycemic conditions activate PSC with a parallel increased production of Ang II (50), and RAS blockade through candesartan or ramiprilat suppress the expression of extracellular matrix proteins in cultured rat PSC (50). More recently, not only high glucose concentrations but also high insulin concentrations were shown to activate PSC, probably through MAPK pathway activation (38).…”