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

Abstract

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-κB/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-κB/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-κB/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-κB/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. Antioxid. Redox Signal. 00, 000-000.

Fenofibrate Improved Interstitial Fibrosis of Renal Allograft through Inhibited Epithelial-Mesenchymal Transition Induced by Oxidative Stress

“…Transplant surgery certainly leads to perioperative acute kidney injury (AKI) from ischemia-reperfusion (IR). It is to be noted here that AKI itself induces ROS generation and cell apoptosis, which contributes to the process of interstitial fibrosis [36]. However, AKI occurred in an early stage after the operation of renal transplant; IF/TA is a long-term and tardy course of the renal allograft.…”

Tetramethylpyrazine Attenuates the Endotheliotoxicity and the Mitochondrial Dysfunction by Doxorubicin via 14-3-3γ/Bcl-2

“…The 14-3-3 γ knockdown model was constructed in Kunming mice via tail vein injection of a recombinant adenovirus containing the shRNA of 14-3-3 γ gene (Genbank ID 22628, target sequence: GCTTCTGAGGCAGC GTATA) as previously described [32]. Briefly, pAD/14-3-3 γ -shRNA adenovirus (2 × 10 11 plaque-forming units/ml, 200 μ l) was injected into the tail vein.…”

Fucoxanthin Attenuates Oxidative Damage by Activating the Sirt1/Nrf2/HO-1 Signaling Pathway to Protect the Kidney from Ischemia-Reperfusion Injury

“…Nrf2 reduces ROS levels by regulating the expression of downstream antioxidant genes HO-1 and NQO1 to prevent oxidative stress-induced tissue damage and apoptosis [25,26]. Numerous studies have shown that the level of intracellular ROS levels after renal I/R is closely related to the degree of renal injury [27,28]. In addition, several studies have confirmed that Sirt1 can contribute to Nrf2 nuclear translocation, enhance the DNA binding activity and transcriptional activity of Nrf2, and upregulate HO-1 expression [29][30][31].…”