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Remote Ischemic Preconditioning Protects Against Ischemia Reperfusion-Induced Oxidative Stress and Acute Kidney Injury by Upregulating GPx3
39 Pages Posted: 23 Aug 2023
More...Abstract
Recent animal experiments and clinical trials indicate that remote ischemic preconditioning (RIPC) confers a protective effect on acute kidney injury (AKI). However, the underlying mechanisms of RIPC alleviating ischemic reperfusion (IR)–induced AKI remains unclear. Here, using a tandem mass tag (TMT) labeling quantitative proteomics on peripheral blood from healthy volunteers subjected to RIPC, we identify a potential renoprotective effector, glutathione peroxidase 3 (GPx3), which is markedly upregulated in the preconditioned skeletal muscle, circulation, and kidney after RIPC. GPx3 is the abundant expression in proximal tubular epithelial cells in the kidney, which was significantly downregulated after renal IR. In vitro, GPx3 overexpression can relieve hypoxia-induced oxidative stress and apoptosis in tubular epithelial cells. In vivo, GPx mimetic ebselen reduces oxidative stress and renal IR injury in mice. Whereas GPx3 deletion abolishes RIPC-offered protective effects on IR-induced oxidative stress and AKI. Furthermore, we demonstrate that RIPC induces upregulation of peroxisome proliferator-activated receptor γ (PPARγ) in the skeletal muscle, pioglitazone, an agonist of PPARγ, upregulates the expression of GPx3 in differentiated C2C12 cells (myotubes). Chromatin immunoprecipitation (ChIP) analysis confirms the direct binding of PPARγ in the GPx3 promoter region, and hypoxia increases the binding of PPARγ to the GPx3 promoter, demonstrating that PPARγ regulates GPx3 expression. Besides, PPARγ overexpression also significantly reduces oxidative stress and apoptosis in hypoxia-treated tubular epithelial cells, however, the protective effects are abolished when GPx3 is silenced. Taken together, our data suggest that RIPC alleviates oxidative stress and AKI through PPARγ/GPx3 pathway, and GPx3 activation may be a novel therapeutic strategy for preventing or treating AKI.
Funding: This article was supported by grants from Clinical Research Plan of Shanghai ShenKang Hospital Development Center (No. SHDC2020CR2022B); Special Fund for Clinical Research of Zhongshan Hospital, Fudan University, 2018; National Natural Science Foundation of China grant 82170695 (to Ping Jia); Science and Technology Commission of Shanghai (14DZ2260200); Shanghai Municipal Key Clinical Specialty Grant (shslczdzk02501).
Declaration of Interest: All authors have declared that there are no conflicts of interest, financial or otherwise.
Ethical Approval: This study was conducted with the permission of the ethics committee of Fudan University. Written consent was obtained from each healthy volunteers. The animal study was approved by the Institutional Animal Care and Use Committee of Zhongshan Hospital Fudan University (approval number: ZS2018-12805). The animals were handled according to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, Bethesda, MD, USA).
Keywords: remote ischemic preconditioning, acute kidney injury, glutathione peroxidase 3, oxidative stress
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