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

Vitamin D/Vitamin D receptor (VDR) has been shown to inhibit the NF-kappa B-mediated inflammatory effects. Upregulation of the NLRP3(Recombinant NLR Family, Pyrin Domain Containing Protein 3)/Caspase-1/GSDMD (Gasdermin D) pathway through NF-kappa b 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 upregulated VDR and decreased expression of NLRP3, GSDMD-N, Cleaved-Caspase-1 and mature Interleukin- 1 beta (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 I kappa B alpha(Inhibitor of NF-kappa B) were decreased and the nuclear level of NF-kappa B p65 of renal tubular cells were increased after cisplatin injury while VDR activation by paricalcitol could reverse upregulation of nuclear NF-kappa B p65 with reduced cell pyroptosis. These data suggested that vitamin D/VDR could alleviate cisplatin-induced acute renal injury partly by inhibiting NF-kappa B-mediated NLRP3/Caspase-1/GSDMD pyroptosis.

Automated summary

The study demonstrated that Vitamin D/VDR could alleviate acute kidney injury induced by cisplatin by inhibiting NF-kappa B-mediated NLRP3/Caspase-1/GSDMD pyroptosis pathway. The protective effects were observed in wild type mice but were eliminated in VDR knock out mice, suggesting the key role of VDR in the mechanism. Additionally, in vitro experiments using human tubular epithelial cells further supported the findings from animal models.