A new therapeutic approach to diabetic nephropathy: targeting renal hypoxia by inhibition of sodium-glucose co-transport in the proximal tubule
| 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 |
オー ペイ・チェン・コニー 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 |
Granted (Fiscal Year 2019)
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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 / renal hypoxia / SGLT2 inhibitor / dapagliflozin |
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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 Annual Research Achievements |
1)Western blot analysis showed that the vehicle treated diabetic rats had significantly elevated renal cortical HIF-1α compared to control rats, suggesting that the cortex is hypoxic in diabetic rats. HIF-1α levels were significantly less in diabetic rats fed dapagliflozin than in vehicle fed diabetic rats, suggesting that dapagliflozin alleviates cortical hypoxia.
2) The responses (vessel diameter) of renal microvessels to vasodilators, ACh and SNP, after 12 weeks treatment were greater than in vehicle fed diabetic rats.
3)The renal microvessels of diabetic rats appeared to undergo relative constriction in response to nitric oxide synthase and cyclooxygenase blockade even under the effects of SNP clamp. In contrast, diabetic rats treated with dapagliflozin appeared to be relatively well-perfused after NOS and COX blockade. This suggests that dapagliflozin may improve endothelial dysfunction commonly associated with diabetic nephropathy.
4)Following NOS and COX blockade, ACh was infused in rats to determine the status of vasodilatory function mediated by endothelium dependent hyperpolarizing factors (EDHF). The renal microvessels in diabetic rats did not appear to be dilated after infusion of ACh, suggesting that vasodilatory effects of EDHF on the vasculature is diminished in diabetic rats. Treatment of dapagliflozin improved this effect in that the renal microvessels were dilated even when NOS and COX production was blocked/inhibited.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We have conducted most of the animal studies as planned.
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| Strategy for Future Research Activity |
1)Telemetric assessment of renal tissue PO2 in type 2 diabetes.
Hypothesis: Renal hypoxia is an early event in diabetes that drives the development of diabetic nephropathy. Chronic treatment with dapagliflozin ameliorates renal hypoxia, which contributes to its ability to delay development of diabetic nephropathy.
Aim: To determine the effects of chronic treatment with dapagliflozin on renal cortical and medullary tissue oxygenation in a rat model of type 2 diabetes.
2)Renal oxygen delivery and oxygen consumption in type 2 diabetes.
Hypothesis: Dapagliflozin ameliorates hypoxia in early diabetes by blunting hyperfiltration, and in more advanced stages, by enhancing the metabolic efficiency of sodium reabsorption.
Aim: To quantify the impact of dapagliflozin on the determinants of renal oxygenation (oxygen delivery and oxygen consumption) and the factors that govern them (renal blood flow, blood hemoglobin content, GFR, sodium reabsorption, and the metabolic efficiency of sodium reabsorption) in early and advanced diabetes. Additionally, we will characterize the temporal and spatial characteristics of renal hypoxia in diabetes, and how this is altered by dapagliflozin.
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Report
(1 results)
Research Products
(3 results)
