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

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.

Automated summary

Activating transcription factor 4 (ATF4) is a crucial mediator of endoplasmic reticulum stress (ERS) and plays a significant role in acute kidney disease (AKI). Vitamin D receptor (VDR) has been shown to provide renoprotection in rodent models of AKI. This study aimed to investigate the involvement of ATF4 and ERS in the protective effect of VDR against ischemia-reperfusion (I/R) induced AKI. The results demonstrated that VDR agonist paricalcitol and VDR overexpression reduced renal injury and apoptosis by decreasing ATF4 expression and attenuating ERS. Conversely, VDR deletion resulted in increased ATF4, exacerbated ERS, and worsened renal injury in I/R mice models. Furthermore, ATF4 partially abolished the protective effect of paricalcitol against ERS and apoptosis induced by Tunicamycin, while inhibition of ATF4 enhanced the protective effect of paricalcitol. Bioinformatics analysis and experimental assays confirmed the potential binding sites of VDR on the ATF4 promoter sequence. In conclusion, VDR attenuates I/R-induced AKI by suppressing ERS through transcriptional regulation of ATF4.