Vitamin D receptor attenuate ischemia-reperfusion kidney injury via inhibiting ATF4.
Shiqi TangXueqin WuQing DaiZhi LiShikun YangYan LiuBin YiJianwen WangQin LiaoWei ZhangHao ZhangPublished in: Cell death discovery (2023)
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.
Keyphrases
- endoplasmic reticulum stress
- induced apoptosis
- transcription factor
- high glucose
- diabetic rats
- acute kidney injury
- drug induced
- type diabetes
- oxidative stress
- cell proliferation
- signaling pathway
- gene expression
- endothelial cells
- metabolic syndrome
- liver failure
- cell cycle arrest
- skeletal muscle
- high throughput
- risk assessment
- genome wide
- human health
- intensive care unit
- dna methylation
- crispr cas
- diffuse large b cell lymphoma
- insulin resistance