Abstract
We previously proposed that hyperglycemia-induced mitochondrial reactive oxygen species (mtROS) generation is a key event in the development of diabetic complications. Interestingly, some common aspects exist between hyperglycemia and hypoxia-induced phenomena. Thus, hyperglycemia may induce cellular hypoxia, and this phenomenon may also be involved in the pathogenesis of diabetic complications. In endothelial cells (ECs), cellular hypoxia increased after incubation with high glucose (HG). A similar phenomenon was observed in glomeruli of diabetic mice. HG-induced cellular hypoxia was suppressed by mitochondria blockades or manganese superoxide dismutase (MnSOD) overexpression, which is a specific SOD for mtROS. Overexpression of MnSOD also increased the expression of aquaporin-1 (AQP1), a water and oxygen channel. AQP1 overexpression in ECs suppressed hyperglycemia-induced cellular hypoxia, endothelin-1 and fibronectin overproduction, and apoptosis. Therefore, hyperglycemia-induced cellular hypoxia and mtROS generation may promote hyperglycemic damage in a coordinated manner.
MeSH terms
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8-Hydroxy-2'-Deoxyguanosine
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Animals
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Apoptosis / drug effects
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Blotting, Western
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Cattle
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Cell Hypoxia
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Cell Line
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Deoxyguanosine / analogs & derivatives
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Deoxyguanosine / biosynthesis
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Diabetes Mellitus, Experimental / complications
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Diabetes Mellitus, Experimental / metabolism
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelin-1 / genetics
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Endothelin-1 / metabolism
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Fibronectins / genetics
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Fibronectins / metabolism
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Glucose / pharmacology
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Hyperglycemia / complications
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Hyperglycemia / metabolism*
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Hypoxia / metabolism
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitochondria / metabolism*
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Reactive Oxygen Species / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
Substances
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Endothelin-1
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Fibronectins
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Reactive Oxygen Species
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8-Hydroxy-2'-Deoxyguanosine
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Superoxide Dismutase
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Deoxyguanosine
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Glucose
Grants and funding
This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Japan (no. 26461340 to TN and no. 15K09393 to DK). The URL of the funder is
https://www.jsps.go.jp/english/e-grants/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.