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

Xueqin Wu, Shiqi Tang, Qing Dai, Bin Yi, Shikun Yang, Jian Sun, Yong Zhong, Wei Lin, Jun Liu, Yan Liu, Jianwen Wang, Jishi Liu, Qin Liao, Wei Zhang, Hao Zhang

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2023 Feb

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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. © 2022 Federation of American Societies for Experimental Biology.

Citation

Xueqin Wu, Shiqi Tang, Qing Dai, Bin Yi, Shikun Yang, Jian Sun, Yong Zhong, Wei Lin, Jun Liu, Yan Liu, Jianwen Wang, Jishi Liu, Qin Liao, Wei Zhang, Hao Zhang. Vitamin D-vitamin D receptor alleviates oxidative stress in ischemic acute kidney injury via upregulating glutathione peroxidase 3. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2023 Feb;37(2):e22738