Reducing Oxidative Stress and Inflammation by Pyruvate Dehydrogenase Kinase 4 Inhibition Is Important in Prevention of Renal Ischemia-Reperfusion Injury in Diabetic Mice

초록

Background: Reactive oxygen species (ROS) and inflammation are reported to have a fundamental role in the pathogenesis of ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury. The present study investigated the role of pyruvate dehydrogenase kinase 4 (PDK4) in ROS production and inflammation following IR injury. Methods: We used a streptozotocin-induced diabetic C57BL6/J mouse model, which was subjected to IR by clamping both renal pedicles. Cellular apoptosis and inflammatory markers were evaluated in NRK-52E cells and mouse primary tubular cells after hypoxia and reoxygenation using a hypoxia work station. Results: Following IR injury in diabetic mice, the expression of PDK4, rather than the other PDK isoforms, was induced with a marked increase in pyruvate dehydrogenase E1 alpha (PDHE1 alpha) phosphorylation. This was accompanied by a pronounced ROS activation, as well as tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL -6), interleukin-13 (IL -13), and monocyte chemoattractant protein -1 (MCP -1) production. Notably, sodium dichloroacetate (DCA) attenuated renal IR injury -induced apoptosis which can be attributed to reducing PDK4 expression and PDHE1 alpha phosphorylation levels. DCA or shPdk4 treatment reduced oxidative stress and decreased TNF-alpha, IL -6, IL -13, and MCP -1 production after IR or hypoxia-reoxygenation injury. Conclusion: PDK4 inhibition alleviated renal injury with decreased ROS production and inflammation, supporting a critical role for PDK4 in IR mediated damage. This result indicates another potential target for reno-protection during IR injury; accordingly, the role of PDK4 inhibition needs to be comprehensively elucidated in terms of mitochondrial function during renal IR injury.

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