High glucose activates rat pancreatic stellate cells through protein kinase C and p38 mitogen-activated protein kinase pathway.
OBJECTIVE
Hyperglycemia is implicated in fibrosis in many organs. Exocrine and endocrine pancreas are closely linked both anatomically and physiologically, and pathological conditions in the exocrine gland can cause impairment of endocrine function and vice versa. Chronic pancreatitis causes pancreatic fibrosis and sometimes results in diabetes mellitus. Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrogenesis. However, the effects of high glucose concentrations on PSC activation have not been fully elucidated.


METHODS
Cultured PSCs were incubated in the presence of various concentrations of glucose. Pancreatic stellate cell proliferation, alpha-smooth muscle actin (alpha-SMA) expression, and collagen production were determined by colorimetric conversion assay, Western blot analysis, and Sirius red dye binding assay, respectively.


RESULTS
High glucose concentrations significantly increased PSC proliferation, alpha-SMA expression, and collagen type I production in PSCs. High glucose concentrations activated protein kinase C (PKC) in PSCs, and PKC inhibitor GF109203X inhibited glucose-stimulated PSC proliferation, alpha-SMA expression, and collagen secretion. High glucose also activated p38 mitogen-activated protein kinase (MAPK) in PSCs, and p38 MAPK inhibitor SB203580 inhibited glucose-stimulated collagen secretion.


CONCLUSIONS
Our results indicate that high glucose concentrations stimulate PSC activation via PKC-p38 MAP kinase pathway and suggest that high glucose may aggravate pancreatic fibrosis.
Nomiyama
Yoko
Y
Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan, School of Medicine, Kitakyushu, Japan.
Tashiro
Mitsuo
M
Yamaguchi
Taizo
T
Watanabe
Shiro
S
Taguchi
Masashi
M
Asaumi
Hiroshi
H
Nakamura
Hayato
H
Otsuki
Makoto
M
D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D003094:Collagen; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate