HIF‐1α ameliorates tubular injury in diabetic nephropathy via HO‐1–mediated control of mitochondrial dynamics
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- Na Jiang
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Hao Zhao
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Yachun Han
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Li Li
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Shan Xiong
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Lingfeng Zeng
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Ying Xiao
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Ling Wei
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Xiaofen Xiong
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Peng Gao
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Ming Yang
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Yu Liu
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
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- Lin Sun
- Department of Nephrology The Second Xiangya Hospital of Central South University Changsha China
抄録
<jats:title>Abstract</jats:title><jats:sec><jats:title>Objectives</jats:title><jats:p>In diabetic nephropathy (DN), hypoxia‐inducible factor‐1α (HIF‐1α) activation in tubular cells plays an important protective role against kidney injury. The effects may occur via the target genes of HIF‐1α, such as haem oxygenase‐1 (HO‐1), but the exact mechanisms are incompletely understood.</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p>Mice with proximal tubule‐specific knockout of HIF‐1α (PT‐HIF‐1α<jats:sup>−/−</jats:sup> mice) were generated, and diabetes was induced in these mice by streptozotocin (STZ) injection. In addition, to mimic a hypoxic state, cobaltous chloride (CoCl<jats:sub>2</jats:sub>) was applied to HK‐2 cells.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Our study first verified that conditional knockout of HIF‐1α worsened tubular injury in DN; additionally, aggravated kidney dysfunction, renal histopathological alterations, mitochondrial fragmentation, ROS accumulation and apoptosis were observed in diabetic PT‐HIF‐1α<jats:sup>−/−</jats:sup> mice. In vitro study showed that compared to control group, HK‐2 cells cultured under hypoxic ambiance displayed increased mitochondrial fragmentation, ROS production, mitochondrial membrane potential loss and apoptosis. These increases were reversed by overexpression of HIF‐1α or treatment with a HO‐1 agonist. Importantly, cotreatment with a HIF‐1α inhibitor and a HO‐1 agonist rescued the HK‐2 cells from the negative impacts of the HIF‐1α inhibitor.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>These data revealed that HIF‐1α exerted a protective effect against tubular injury in DN, which could be mediated via modulation of mitochondrial dynamics through HO‐1 upregulation.</jats:p></jats:sec>
収録刊行物
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- Cell Proliferation
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Cell Proliferation 53 (11), 2020-09-25
Wiley