| Project/Area Number |
19K17759
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53040:Nephrology-related
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
Ow Connie 国立研究開発法人国立循環器病研究センター, 研究所, 流動研究員 (30824221)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | Diabetic nephropathy / SGLT2 inhibitor / renal hypoxia / diabetic nephropathy / dapagliflozin / kidney |
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| Outline of Research at the Start |
Tissue hypoxia, due in part to excessive and inefficient utilization of oxygen, is likely a major factor in the pathogenesis of diabetic nephropathy. We hypothesize that inhibiting SGLT2 will reduce excessive oxygen consumption and thereby preventing hypoxia and the development of nephropathy.
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| Outline of Final Research Achievements |
The renal cortex of rats with type 2 diabetes is hypoxic in early diabetes but does not worsen with severity of hyperglycemia. Following acute dapagliflozin treatment, cortical PO2 increased by 87.1 ± 17.5% in the 9 wk old rats and 42.4 ± 8.4% in the 24 wk old rats. This may indicate that the effects of preventing hypoxia maybe greater when treated in early diabetes. The alleviation of tissue hypoxia is due to the significantly greater reductions in renal oxygen consumption, presumably due to the reduction in glucose reabsorption, than alterations in oxygen delivered to the kidney. The alleviation of cortical hypoxia appeared to be sustained with long term treatment of SGLT2 inhibitors as levels of HIF-1a was significantly less than non-treated rats. Further, chronic treatment improved endothelial dysfunction, evident by the observations of well-perfused vessels during vasoconstrictor challenges. Vasodilatory effects of EDHs on the vasculature was restored following treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
We showed that treatment with SGLT2 inhibitors may prevent the glucotoxicity on the kidney as excessive glucose in the circulation is excreted into the urine. In doing so, it relieves the kidney from hypoxia, an effect commonly described to contribute to the severity of diabetic nephropathy.
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