Tubular mitochondrial AKT1 is activated during ischemia reperfusion injury and has a critical role in predisposition to chronic kidney disease.
Tubular mitochondrial AKT1 is activated during ischemia reperfusion injury and has a critical role in predisposition to chronic kidney disease.
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DOI：
10.1016/j.kint.2020.10.038
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发表时间：
2021-04
影响因子：
19.6
通讯作者：
Wang PH
中科院分区：
文献类型：
--
作者：
Lin HY;Chen Y;Chen YH;Ta AP;Lee HC;MacGregor GR;Vaziri ND;Wang PH
肾小管功能障碍可导致急性肾损伤和向慢性肾脏疾病的转变。虽然肾小管线粒体参与了肾功能衰竭的病理生理过程，但其机制尚不清楚。在这里，我们证明了缺血再灌注损伤诱导了肾小管线粒体蛋白激酶B(又称AKT1)的急性移位和激活。我们假设线粒体AKT1信号对急性肾损伤和随后的慢性肾脏疾病的发展具有保护作用。为了验证这一预测，我们使用Cre-Lox策略产生了两个新的肾小管特异性转基因小鼠品系，它们可以诱导表达线粒体靶向的显性阴性AKT1或结构性活性AKT1。线粒体靶向显性阴性AKT1小鼠线粒体AKT1的抑制加重了氮质血症、肾小管损伤、肾纤维化、肾小球硬化，并对缺血再灌注损伤后的存活率产生了负面影响。相反，在线粒体靶向的成分活跃的AKT1小鼠中，增强管状线粒体AKT1信号可以减轻肾脏损伤，保护肾功能，并显著提高缺血再灌注损伤后的存活率(分别为76.9%和20.8%)。当线粒体AKT1被抑制时，肾小管线粒体呼吸解偶联和氧化应激增加，支持线粒体功能障碍在肾功能衰竭的病理生理机制中的作用。因此，我们的研究表明，小管线粒体AKT1信号可能成为开发更好地预防和治疗肾损伤的新策略的新靶点。急性肾损伤(AKI)和随后的慢性肾脏疾病(CKD)是重要的健康问题。我们建立了转基因小鼠模型，并明确了近端肾小管线粒体AKT激活在AKI和CKD中的作用。这种肾脏保护的抢救机制可能代表着一个新的靶点，以开发更好地预防和治疗AKI和CKD的新策略。未来的研究应该证实线粒体AKT信号参与人类肾脏损伤，并探索线粒体AKT1通路中的药物靶点。
Kidney tubular dysfunction contributes to acute kidney injury and to the transition to chronic kidney disease. Although tubular mitochondria have been implicated in the pathophysiology of kidney failure, the mechanisms are not yet clear. Here, we demonstrated that ischemia-reperfusion injury induced acute translocation and activation of mitochondrial protein kinase B (also known as AKT1) in the kidney tubules. We hypothesized that mitochondrial AKT1 signaling protects against the development of acute kidney injury and subsequent chronic kidney disease. To test this prediction, we generated two novel kidney tubule-specific transgenic mouse strains with inducible expression of mitochondria-targeted dominant negative AKT1 or constitutively active AKT1, using a Cre-Lox strategy. Inhibition of mitochondrial AKT1 in mitochondria-targeted dominant negative AKT1 mice aggravated azotemia, tubular injuries, kidney fibrosis, glomerulosclerosis, and negatively impacted survival after ischemia-reperfusion injury. Conversely, enhancing tubular mitochondrial AKT1 signaling in mitochondria-targeted constitutively active AKT1 mice attenuated kidney injuries, protected kidney function, and significantly improved survival after ischemia-reperfusion injury (76.9% vs. 20.8%, respectively). Uncoupled mitochondrial respiration and increased oxidative stress was found in the kidney tubules when mitochondria AKT1 was inhibited, supporting the role of mitochondrial dysfunction in the pathophysiology of kidney failure. Thus, our studies suggest tubular mitochondrial AKT1 signaling could be a novel target to develop new strategies for better prevention and treatment of kidney injury. Acute kidney injury (AKI) and subsequent development of chronic kidney disease (CKD) are significant health issues. We developed transgenic mouse models and defined the role of proximal renal tubule mitochondria AKT activation in AKI and CKD. This rescue mechanism of renal protection may represent a novel target to develop new strategies for better prevention and treatment of AKI and CKD. Future studies should confirm the involvement of mitochondrial AKT signaling in human kidney injury and explore druggable targets in the mitochondrial AKT1 pathway.
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DOI：
10.1053/j.ajkd.2018.03.028
发表时间：
2018-12
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
--
作者：
Lee SA;Cozzi M;Bush EL;Rabb H
通讯作者：
Rabb H
DOI：
10.1016/b978-0-12-394309-5.00006-7
发表时间：
2012
影响因子：
--
作者：
Kalogeris, Theodore;Baines, Christopher P.;Krenz, Maike;Korthuis, Ronald J.
通讯作者：
Korthuis, Ronald J.
影响因子：
3.3
作者：
Li SY;Susztak K
通讯作者：
Susztak K
DOI：
10.1124/jpet.114.214700
发表时间：
2014-08-01
影响因子：
3.5
作者：
Garrett, Sara M.;Whitaker, Ryan M.;Schnellmann, Rick G.
通讯作者：
Schnellmann, Rick G.
影响因子：
19.6
作者：
通讯作者：
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