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Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury.

ABSTRACT: 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-?B/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-?B/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-?B/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-?B/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.

SUBMITTER: Chen C

PROVIDER: S-EPMC7364332 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury.

Chen Chaojin C Yao Weifeng W Wu Shan S Zhou Shaoli S Ge Mian M Gu Yu Y Li Xiang X Chen Guihua G Bellanti Joseph A JA Zheng Song Guo SG Yuan Dongdong D Hei Ziqing Z

Antioxidants & redox signaling 20180830 12

<b><i>Aims:</i></b> 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 a ...[more]

PMID: 29790387

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Project description:BackgroundIschemia-reperfusion (I/R)-induced acute kidney injury (AKI) not only prolongs the length of hospital stay, but also seriously affects the patient's survival rate. Although our previous investigation has verified that reactive oxygen species (ROS) transferred through gap junction composed of connexin32 (Cx32) contributed to AKI, its underlying mechanisms were not fully understood and viable preventive or therapeutic regimens were still lacking. Among various mechanisms involved in organs I/R-induced injuries, endoplasmic reticulum stress (ERS)-related apoptosis is currently considered to be an important participant. Thus, in present study, we focused on the underlying mechanisms of I/R-induced AKI, and postulated that Cx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI.MethodsWe established renal I/R models with Cx32+/+ and Cx32-/- mice, which underwent double kidneys clamping and recanalization. ROS scavenger (N-acetylcysteine, NAC) and ERS inhibitors (4-phenyl butyric acid, 4-PBA, and tauroursodeoxycholic acid, TUDCA) were used to decrease the content of ROS and attenuate ERS activation, respectively.ResultsRenal damage was progressively exacerbated in a time-dependent manner at the reperfusion stage, that was consistent with the alternation of ERS activation, including glucose regulated protein 78 (BiP/GRP78), X box-binding protein1, and C/EBP homologous protein expression. TUDCA or 4-PBA application attenuated I/R-induced ERS activation and protected against renal tubular epithelial cells apoptosis and renal damage. Cx32 deficiency decreased ROS generation and distribution between the neighboring cells, which attenuated I/R-induced ERS activation, and improved cell apoptosis and renal damage.ConclusionCx32 mediated ROS/ERS/apoptosis signal pathway activation played an important part in I/R-induced AKI. Cx32 deficiency, ROS elimination, and ERS inhibition all could protect against I/R-induced AKI.

Project description:BackgroundRenal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI.MethodsMale Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1-72 h reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.ResultsTreprostinil significantly reduced peak elevated serum creatinine (SCr) levels and accelerated normalization relative to IRI-placebo (p < 0.0001). Treatment with treprostinil also inhibited IRI-mediated renal apoptosis, mitochondrial oxidative injury (p < 0.05), and the release of cytochrome c (p < 0.01) vs. IRI-placebo. In addition, treprostinil preserved renal mitochondrial DNA copy number (p < 0.0001) and renal ATP levels (p < 0.05) to nearly those of sham-operated animals. Non-targeted semi-quantitative proteomics showed reduced levels of ATP synthase subunits in the IRI-placebo group which were restored to sham levels by treprostinil treatment (p < 0.05). Furthermore, treprostinil reduced renal IRI-induced upregulated Drp1 and pErk protein levels, and restored Sirt3 and Pgc-1α levels to baseline (p < 0.05).ConclusionsTreprostinil reduces mitochondrial-mediated renal apoptosis, inhibits mitochondria fission, and promotes mitochondria fusion, thereby accelerating mitochondrial recovery and protecting renal proximal tubules from renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI.

Dataset Information

Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury.

Publications

Crosstalk Between Connexin32 and Mitochondrial Apoptotic Signaling Pathway Plays a Pivotal Role in Renal Ischemia Reperfusion-Induced Acute Kidney Injury.

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