High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase.
BACKGROUND
Nonalcoholic steatohepatitis is a clinicopathologic condition that may progress to liver fibrosis. Hyperglycemia is supposed to be one of the factors inducing hepatic fibrogenesis, but the mechanism has not been fully clarified. Oxidative stress is increasingly found in patients with diabetes/hyperglycemia in which conditions reactive oxygen species (ROS) are produced.


METHODS
We performed experiments using hepatic stellate cells (HSCs) in culture in order to confirm the effect of high glucose concentrations on cell proliferation, type I collagen production, ROS production and activation of mitogen-activated protein (MAP) kinase pathway.


RESULTS
High glucose stimulated cell growth of HSCs and up-regulated the levels of activated/phosphorylated extracellular signal-regulated kinase 1/2 and free radical production in HSCs. The MAP kinase phosphorylation and cell proliferation were suppressed by diphenylene iodonium chloride, an NADPH oxidase inhibitor, and by calphostin C, a protein kinase C (PKC)-specific inhibitor. Increased type I collagen mRNA and protein levels were also observed in HSCs at high glucose concentrations.


CONCLUSIONS
Our findings indicate that high glucose concentrations may stimulate ROS production through PKC-dependent activation of NADPH oxidase, and induce MAP kinase phosphorylation subsequent to proliferation and type I collagen production by HSCs.
Sugimoto
Rie
R
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Enjoji
Munechika
M
Kohjima
Motoyuki
M
Tsuruta
Satoshi
S
Fukushima
Marie
M
Iwao
Masataka
M
Sonta
Toshiyo
T
Kotoh
Kazuhiro
K
Inoguchi
Toyoshi
T
Nakamuta
Makoto
M
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D024042:Collagen Type I / Q000096:biosynthesis*; D004789:Enzyme Activation; D005609:Free Radicals; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D019255:NADPH Oxidases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species
D024042:Collagen Type I; D005609:Free Radicals; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D001973:Bromodeoxyuridine