Vitamin D–vitamin D receptor alleviates oxidative stress in ischemic acute kidney injury via upregulating glutathione peroxidase 3

Abstract Vitamin D receptor was previously reported to be protective in acute kidney injury (AKI) with the mechanism unclear, while the role of renal localized glutathione peroxidase 3 (GPX3) was not illustrated. The present study aims to investigate the role of GPX3 as well as its correlation with vitamin D–vitamin D receptor (VD–VDR) in ischemia–reperfusion (I/R)‐induced renal oxidative stress injury. We showed that the expression of GPX3 and VDR were consistently decreased in renal tissues of I/R‐related AKI patients and mice models. VDR agonist paricalcitol could reverse GPX3 expression and inhibit oxidative stress in I/R mice or hypoxia‐reoxygenation (H/R) insulted HK‐2 cells. VDR deficiency resulted in aggregated oxidative stress and severer renal injury accompanied by further decreased renal GPX3, while tubular‐specific VDR overexpression remarkably reduced I/R‐induced renal injury with recovered GPX3 in mice. Neither serum selenium nor selenoprotein P was affected by paricalcitol administration nor Vdr modification in vivo. In addition, inhibiting GPX3 abrogated the protective effects of VD–VDR in HK‐2 cells, while GPX3 overexpression remarkably attenuated H/R‐induced oxidative stress and apoptosis. Mechanistic probing revealed the GPX3 as a VDR transcriptional target. Our present work revealed that loss of renal GPX3 may be a hallmark that promotes renal oxidative stress injury and VD–VDR could protect against I/R‐induced renal injury via inhibition of oxidative stress partly by trans‐regulating GPX3 . In addition, maintenance of renal GPX3 could be a therapeutic strategy for ischemic AKI.