Abstract
Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death. However, the role of ferroptosis, a newly discovered form of oxidative cell death, has not been evaluated widely. Pannexin 1 (PANX1), an ATP-releasing pathway family protein, has pro-apoptotic effects during kidney injury. Here, we demonstrate that PANX1 deletion protects against renal IRI by regulating ferroptotic cell death. Panx1 knockout mice subjected to renal IRI had decreased plasma creatinine, malondialdehyde (MDA) levels in kidney tissues, and tubular cell death (visible as decreased TUNEL-positive renal tubular cells) compared with WT mice. In cultured human kidney 2 (HK-2) cells, silenced Panx1 expression significantly attenuated ferroptotic lipid peroxidation and iron accumulation induced by the ferroptosis inducer erastin. Moreover, the Panx1 silencing significantly modulated ferroptosis-related protein expression. Furthermore, Panx1 deletion induced the expression of a cytoprotective chaperone, heme oxygenase-1 (HO-1), and inhibited ferroptinophagy via the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. In summary, Panx1 deletion protects against renal IRI by attenuating MAPK/ERK activation in a ferroptotic pathway. Our findings provide critical insights into the role of PANX1 in ferroptotic cell death and highlight a potential therapeutic target for the management of acute kidney injury (AKI) during the perioperative period.
Highlights
Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death
The most important finding of this study is the identification of an important role of Panx1 in regulating ferroptosis in the kidney, whereby the absence of the panx1 channel protects renal tubular epithelial cells from erastin-induced ferroptosis and kidney injury for IRI
Previous studies have reported that P2Y7R, a receptor of panx1, triggered cell death that can be reversed by inhibition of ferroptosis production of NADPH oxidase– generated reactive oxygen species (ROS), which suggests a role of panx1 in ferroptosis [29, 30]
Summary
Renal ischemia/reperfusion injury (IRI) is a significant challenge in perioperative medicine and is related to oxidative programmed cell death. Ferroptosis, a newly discovered form of programmed, nonapoptotic cell death triggered by oxidative damage, has not been widely investigated in IRI-AKI. Ferroptosis is an iron-dependent type of programmed cell death, triggered by lipid peroxide accumulation in the context of increased reactive oxygen species (ROS) generation and inactivation of GSH peroxidase 4 (GPX4), a GSH-dependent enzyme that prevents lipid peroxidation [5]. It can be triggered by structurally diverse small molecules (e.g. erastin, sulfasalazine, and RSL3) and prevented by lipophilic antioxidants (CoQ10, vitamin E, ferrostatins, and liproxstatins) (6 –9). Our findings provide new insights to understand the tracellular signal–regulated kinase kinase; H&E, hematoxylin and eosin; 7-AAD, 7-aminoactinomycin D; Scr, serum creatinine
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