Loss of GPX3 Promotes AKI by Aggravating Peritubular Oxidative Stress and Mitochondrial Dysfunction

Background: Acute kidney injury (AKI) is a clinical syndrome of rapidly diminishing renal function which represents a major global public health challenge. The core pathological event in AKI is the tubular injury, manifested mainly by sublethal and lethal damage to the tubular epithelial cells. However, the mechanisms of renal tubular injury remain elusive. In the present study, we demonstrate that AKI leads to the loss of the extracellular matrix protein GPX3, which triggers an imbalance in mitochondrial homeostasis promoting renal tubular injury. Methods: Bilateral ischemia-reperfusion and cisplatin were used to induce AKI. Decellularized kidney tissue scaffold (dKTS) was prepared. GPX3 loss on the effect of tubular injury and mitochondrial homeostasis was studied in vitro. Mice with overexpression of GPX3 or knockout of GPX3 gene were used in vivo. Nano-selenium treatment was performed in vivo. Clinical data from UK Biobank was used for human studies. Results: In vivo experiments showed that GPX3 expression was down-regulated in multiple AKI models. Using decellularized kidney tissue scaffold combined with in vitro experiments, we demonstrated that the GPX3-loss extracellular microenvironment induced oxidative stress and apoptosis in renal tubular cells. Overexpression of GPX3 ameliorated renal function and tubular cell apoptosis and restored mitochondrial homeostasis in IRI mice. Knockdown of GPX3 aggravated renal dysfunction and tubular cell apoptosis, and disrupted mitochondrial homeostasis in IRI mice. Mechanistically, loss of GPX3 activated NOX2/NOX4/ERK signaling cascade that promoted mitochondrial dysfunction causing tubular injury. Tail vein injection of nanoparticle containing selenium restored GPX3 expression and ameliorated kidney injury in AKI mice. Clinical analysis of UK Biobank data demonstrated that dietary selenium was negatively associated with the risk of new-onset AKI. Conclusion: This study showed that the loss of GPX3 after AKI generates an extracellular microenvironment of oxidative stress, leading to mitochondrial dysfunction and tubular cell apoptosis. Nanoparticle-based selenium supplementation is a promising therapeutic strategy to effectively ameliorate AKI and restore renal function. Funding: Government Support – Non-U.S.