High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase
Article first published online: 28 JUN 2005
Volume 25, Issue 5, pages 1018–1026, October 2005
How to Cite
Sugimoto, R., Enjoji, M., Kohjima, M., Tsuruta, S., Fukushima, M., Iwao, M., Sonta, T., Kotoh, K., Inoguchi, T. and Nakamuta, M. (2005), High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase. Liver International, 25: 1018–1026. doi: 10.1111/j.1478-3231.2005.01130.x
- Issue published online: 14 JUL 2005
- Article first published online: 28 JUN 2005
- Received 24 November 2004, accepted 16 February 2005
- hepatic stellate cells;
Abstract: 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.