Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway

• Published in: The Journal of steroid biochemistry and molecular biology 2021-02, Vol.206, p.105789-105789, Article 105789
• Main Authors: Jiang, Siqing, Zhang, Hao, Li, Xin, Yi, Bin, Huang, Lihua, Hu, Zhaoxin, Li, Aimei, Du, Jie, Li, Yanchun, Zhang, Wei
• Format: Article
• Language: English
• Subjects: Acute kidney injury; Acute Kidney Injury - chemically induced; Acute Kidney Injury - drug therapy; Acute Kidney Injury - genetics; Acute Kidney Injury - pathology; Animals; Caspase 1 - genetics; Caspase-1; Cell culture; Cell death; Cisplatin; Cisplatin - adverse effects; Epithelial cells; Ergocalciferols - pharmacology; Gene Expression Regulation - drug effects; Humans; Inflammation; Intracellular Signaling Peptides and Proteins - genetics; Kidney - drug effects; Kidney - injuries; Kidney - pathology; Mice; Mice, Knockout; NF-κB pathway; NF-κB protein; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; Phenotypes; Phosphate-Binding Proteins - genetics; Pyrin protein; Pyroptosis; Pyroptosis - drug effects; Pyroptosis - genetics; Pyroptosis pathway; Receptors, Calcitriol - genetics; Renal function; Vitamin D; Vitamin D - pharmacology; Vitamin D receptor; Vitamin D receptors
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2020.105789

•The experiment found thatvitamin D / VDR can inhibiting cell pyrolysis in cisplatin-induced AKI.•The experiment used tubule-specific overexpression mice in cisplatin-induced AKI.•The experiment separately observed the role of VDR in cisplatin-induced AKI. Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-κB-mediated inflammatory effects. Up-regulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-κb is one of the key mechanisms leading to pyroptosis. This study aims to explore the effects of vitamin D/VDR on the pyroptosis pathway in cisplatin induced acute kidney injury (AKI) models. Our results showed that in wide type mice, renal function loss, tissue injury and cell death induced by cisplatin were alleviated by pretreatment of high-dose paricalcitol(a VDR agonist) accompanied with up-regulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1β (features of pyroptosis). While, in VDR knock out mice, cisplatin induced more severer renal injury and further increased pyroptosis related protein than the wild type mice and the effect of paricalcitol were also eliminated. In tubular cell specific VDR-over expressing mice, those renal injury index as well as pyroptosis phenotype were significantly reduced by low-dose paricalcitol pretreatment with upregulated VDR expression compared with WT mice. In vitro data using gain and lose function experiments in Human tubular epithelial cell (HK-2) were consistent with the observation as in vivo work. Our further experiments in both animal and cell culture work has found that the level of IκBα(Inhibitor of NF-κB) were decreased and the nuclear level of NF-κB p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse up-regulation of nuclear NF-κB p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-κB-mediated NLRP3/Caspase-1/GSDMD pyroptosis.