PMID- 29790387 OWN - NLM STAT- MEDLINE DCOM- 20200818 LR - 20231213 IS - 1557-7716 (Electronic) IS - 1523-0864 (Print) IS - 1523-0864 (Linking) VI - 30 IP - 12 DP - 2019 Apr 20 TI - Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury. PG - 1521-1538 LID - 10.1089/ars.2017.7375 [doi] AB - Aims: Perioperative acute kidney injury (AKI) resulting from renal ischemia reperfusion (IR) is not conducive to the postoperative surgical recovery. Our previous study demonstrated that reactive oxygen species (ROS) transmitted by gap junction (GJ) composed of connexin32 (Cx32) contributed to AKI. However, the precise underlying pathophysiologic mechanisms were largely unknown. This study focuses on the underlying mechanisms related to ROS transmitted by Cx32 responsible for AKI aggravation. Results: In a set of in vivo studies, renal IR was found to cause severe impairment in renal tissues with massive ROS generation, which occurred contemporaneously with activation of NF-kappaB/p53/p53 upregulated modulator of apoptosis (PUMA)-mediated mitochondrial apoptosis pathways. Cx32 deficiency alleviated renal IR-induced AKI, and simultaneously attenuated ROS generation and distribution in renal tissues, which further inhibited NF-kappaB/p53/PUMA-mediated mitochondrial apoptotic pathways. Correspondingly, in a set of in vitro studies, hypoxia reoxygenation (HR)-induced cellular injury, and cell apoptosis in both human kidney tubular epithelial cells (HK-2s) and rat kidney tubular epithelial cells (NRK52Es) were significantly attenuated by Cx32 inhibitors or Cx32 gene knockdown. More importantly, Cx32 inhibition not only decreased ROS generation and distribution in human or rat kidney tubular epithelial cells but also inhibited its downstream NF-kappaB/p53/PUMA-mediated mitochondrial apoptotic pathway activation. Innovation and Conclusion: This is the first identification of the underlying mechanisms of IR-induced renal injury integrally which demonstrates the critical role played by Cx32 in IR-induced AKI. Moreover, GJ composed of Cx32 manipulates ROS generation and distribution between neighboring cells, and alters activation of NF-kappaB/p53/PUMA-mediated mitochondrial apoptotic pathways. Both inhibiting Cx32 function and scavenging ROS effectively reduce mitochondrial apoptosis and subsequently attenuate AKI, providing effective strategies for kidney protection. FAU - Chen, Chaojin AU - Chen C AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Yao, Weifeng AU - Yao W AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Wu, Shan AU - Wu S AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Zhou, Shaoli AU - Zhou S AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Ge, Mian AU - Ge M AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Gu, Yu AU - Gu Y AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Li, Xiang AU - Li X AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Chen, Guihua AU - Chen G AD - Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Bellanti, Joseph A AU - Bellanti JA AD - Departments of Pediatrics and Microbiology-Immunology, Georgetown University Medical Center, Washington, District of Columbia. FAU - Zheng, Song Guo AU - Zheng SG AD - Department of Medicine, Milton S Hershey Medical Center, Penn State University, State College, Pennsylvania. FAU - Yuan, Dongdong AU - Yuan D AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. FAU - Hei, Ziqing AU - Hei Z AD - Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China. AD - Department of Anesthesiology, Yuedong Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Meizhou, People's Republic of China. LA - eng GR - R01 AR059103/AR/NIAMS NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180830 PL - United States TA - Antioxid Redox Signal JT - Antioxidants & redox signaling JID - 100888899 RN - 0 (Connexins) RN - 0 (Reactive Oxygen Species) SB - IM MH - Acute Kidney Injury/*genetics/metabolism MH - Animals MH - Apoptosis MH - Cell Line MH - Connexins/*genetics/metabolism MH - Disease Models, Animal MH - Gene Knockdown Techniques MH - Humans MH - Male MH - Mice MH - Mitochondria/*metabolism MH - Rats MH - Reactive Oxygen Species/metabolism MH - Reperfusion Injury/*genetics/metabolism MH - Gap Junction beta-1 Protein PMC - PMC7364332 OTO - NOTNLM OT - ROS OT - acute kidney injury OT - connexin32 OT - mitochondrial apoptosis OT - renal ischemia reperfusion COIS- No competing financial interests exist. EDAT- 2018/05/24 06:00 MHDA- 2020/08/19 06:00 PMCR- 2020/04/20 CRDT- 2018/05/24 06:00 PHST- 2018/05/24 06:00 [pubmed] PHST- 2020/08/19 06:00 [medline] PHST- 2018/05/24 06:00 [entrez] PHST- 2020/04/20 00:00 [pmc-release] AID - 10.1089/ars.2017.7375 [pii] AID - 10.1089/ars.2017.7375 [doi] PST - ppublish SO - Antioxid Redox Signal. 2019 Apr 20;30(12):1521-1538. doi: 10.1089/ars.2017.7375. Epub 2018 Aug 30.