Mitochondrial fumarate promotes ischemia/reperfusion‐induced tubular injury

急性肾损伤 缺血 再灌注损伤 活性氧 线粒体 谷胱甘肽 医学 化学 细胞生物学 药理学 生物 生物化学 内科学
作者
Zuo‐Lin Li,Man Huang,Meng‐Yao Yu,Daotai Nie,Siyi Fu,Jiehui Di,Ting Lan,Bi‐Cheng Liu,Qiuli Wu
出处
期刊:Acta Physiologica [Wiley]
卷期号:240 (4)
标识
DOI:10.1111/apha.14121
摘要

Abstract Aim Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. Methods ESI‐QTRAP‐MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. Results We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition‐mediated tubule injury recovery. Reactive oxygen species/NF‐κB signaling activation played a vital role in fumarate‐mediated tubule injury. Conclusion Our studies demonstrated that the mitochondrial‐derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate‐mediated ROS/NF‐κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.
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