Vitamin D receptor attenuate ischemia-reperfusion kidney injury via inhibiting ATF4

Shiqi Tang; Xueqin Wu; Qing Dai; Zhi Li; Shikun Yang; Yan Liu; Bin Yi; Jianwen Wang; Qin Liao; Wei Zhang; Hao Zhang

doi:10.1038/s41420-023-01456-4

Vitamin D receptor attenuate ischemia-reperfusion kidney injury via inhibiting ATF4

Cell Death Discov. 2023 May 12;9(1):158. doi: 10.1038/s41420-023-01456-4.

Authors

Shiqi Tang^{1

2}, Xueqin Wu^{1

2}, Qing Dai^{1

2}, Zhi Li^{1

2}, Shikun Yang^{1

2}, Yan Liu^{1

2}, Bin Yi^{1

2}, Jianwen Wang^#^{3

4}, Qin Liao⁵, Wei Zhang^#^{6

7}, Hao Zhang^#^{8

9}

Affiliations

¹ Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
² The Critical Kidney Disease Research Center of Central South University, Changsha, Hunan Province, China.
³ Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. jwwangdoc@163.com.
⁴ The Critical Kidney Disease Research Center of Central South University, Changsha, Hunan Province, China. jwwangdoc@163.com.
⁵ Department of Anesthesiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
⁶ Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. weizhangxy@126.com.
⁷ The Critical Kidney Disease Research Center of Central South University, Changsha, Hunan Province, China. weizhangxy@126.com.
⁸ Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. zhanghaoliaoqing@163.com.
⁹ The Critical Kidney Disease Research Center of Central South University, Changsha, Hunan Province, China. zhanghaoliaoqing@163.com.

^# Contributed equally.

Abstract

Activating transcription factor 4 (ATF4) is one of the key effectors of endoplasmic reticulum stress (ERS), ATF4/CHOP pathway-mediated ERS plays an important role in the progression of acute kidney disease (AKI). We have previously reported that Vitamin D receptor (VDR) exert renoprotection in rodent AKI models. However, whether ATF4, as well as ERS, is involved in the protective effect of VDR in ischemia-reperfusion (I/R) induced AKI is unknown. Herein, we showed that VDR agonist paricalcitol and VDR overexpression alleviated I/R-induced renal injury and cells apoptosis with decreased ATF4 and attenuated ERS, while VDR deletion significantly resulted in further increased ATF4, more drastic ERS and renal injury in I/R mice models. In addition, paricalcitol remarkably reduced Tunicamycin (TM) induced ATF4 and ERS with attenuated renal injury, while VDR deletion aggravated the above changes in TM mice models. Moreover, overexpression of ATF4 partially abolished the effect of paricalcitol against TM-induced ERS and apoptosis, while inhibition of ATF4 enhanced the protective effect of paricalcitol. Bioinformatics analysis indicated potential VDR binding sites on ATF4 promotor sequence which were further confirmed by ChIP-qPCR and dual-luciferase reporter gene assay. In conclusion, VDR attenuated I/R-induced AKI by suppressing ERS partly via transcriptional regulation of ATF4.