title: 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.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology & Metabolism, The Catholic University of Korea, Seoul.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ko
authors.forename: Oak-Kee
authors.initials: OK
authors.lastname: Hong
authors.forename: Ji-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Yu-Bai
authors.initials: YB
authors.lastname: Ahn
authors.forename: Ki-Ho
authors.initials: KH
authors.lastname: Song
authors.forename: Bong-Yun
authors.initials: BY
authors.lastname: Cha
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Son
authors.forename: Myung-Jun
authors.initials: MJ
authors.lastname: Kim
authors.forename: In-Kyung
authors.initials: IK
authors.lastname: Jeong
authors.forename: Kun-Ho
authors.initials: KH
authors.lastname: Yoon
mesh_terms: D000803:Angiotensin I / Q000502:physiology; D000804:Angiotensin II / Q000096:biosynthesis*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D003094:Collagen / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005353:Fibronectins / Q000096:biosynthesis; D005355:Fibrosis; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology*; D010195:Pancreatitis / Q000503:physiopathology; D017257:Ramipril / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; C526316:CCN2 protein, rat; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor; D003094:Collagen; D000803:Angiotensin I; D005947:Glucose; D017257:Ramipril; C081643:candesartan