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解偶联蛋白-2 的缺失可减少 1 型糖尿病小鼠模型的肾线粒体渗漏呼吸、肾内缺氧和蛋白尿。

Deletion of Uncoupling Protein-2 reduces renal mitochondrial leak respiration, intrarenal hypoxia and proteinuria in a mouse model of type 1 diabetes.

机构信息

Division of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.

出版信息

Acta Physiol (Oxf). 2018 Aug;223(4):e13058. doi: 10.1111/apha.13058. Epub 2018 Mar 15.

Abstract

AIM

Uncoupling protein-2 (UCP-2) can induce mitochondrial uncoupling in the diabetic kidney. Although mitochondrial uncoupling reduces oxidative stress originating from the mitochondria and can be regarded as a protective mechanism, the increased oxygen consumption occurring secondarily to increased mitochondria uncoupling, that is leak respiration, may contribute to kidney tissue hypoxia. Using UCP-2 mice, we tested the hypothesis that UCP-2-mediated leak respiration is important for the development of diabetes-induced intrarenal hypoxia and proteinuria.

METHODS

Kidney function, in vivo oxygen metabolism, urinary protein leakage and mitochondrial function were determined in wild-type and UCP-2 mice during normoglycaemia and 2 weeks after diabetes induction.

RESULTS

Diabetic wild-type mice displayed mitochondrial leak respiration, pronounced intrarenal hypoxia, proteinuria and increased urinary KIM-1 excretion. However, diabetic UCP-2 mice did not develop increased mitochondrial leak respiration and presented with normal intrarenal oxygen levels, urinary protein and KIM-1 excretion.

CONCLUSION

Although functioning as an antioxidant system, mitochondria uncoupling is always in co-occurrence with increased oxygen consumption, that is leak respiration; a potentially detrimental side effect as it can result in kidney tissue hypoxia; an acknowledged unifying pathway to nephropathy. Indeed, this study demonstrates a novel mechanism in which UCP-2-mediated mitochondrial leak respiration is necessary for the development of diabetes-induced intrarenal tissue hypoxia and proteinuria.

摘要

目的

解偶联蛋白 2(UCP-2)可诱导糖尿病肾脏中的线粒体解偶联。虽然线粒体解偶联减少了源自线粒体的氧化应激,可被视为一种保护机制,但继发于线粒体解偶联增加的耗氧量,即漏呼吸,可能导致肾脏组织缺氧。利用 UCP-2 小鼠,我们检验了以下假说,即 UCP-2 介导的漏呼吸对糖尿病诱导的肾内缺氧和蛋白尿的发生发展很重要。

方法

在正常血糖和糖尿病诱导后 2 周,测定野生型和 UCP-2 小鼠的肾功能、体内氧代谢、尿蛋白漏出和线粒体功能。

结果

糖尿病野生型小鼠表现出线粒体漏呼吸、明显的肾内缺氧、蛋白尿和尿 KIM-1 排泄增加。然而,糖尿病 UCP-2 小鼠未发生增加的线粒体漏呼吸,且肾内氧水平、尿蛋白和 KIM-1 排泄正常。

结论

尽管作为抗氧化系统发挥作用,但线粒体解偶联总是伴随着耗氧量的增加,即漏呼吸;这是一种潜在的有害副作用,因为它会导致肾脏组织缺氧;这是公认的导致肾病的统一途径。事实上,本研究证明了一种新的机制,即 UCP-2 介导的线粒体漏呼吸是糖尿病诱导的肾内组织缺氧和蛋白尿发生发展所必需的。

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