MicroRNA‐122 contributes to lipopolysaccharide‐induced acute kidney injury via down‐regulating the vitamin D receptor in the kidney.

Background: Our previous studies showed that vitamin D receptor (VDR) depletion promotes lipopolysaccharide (LPS)‐induced acute kidney injury (AKI) in mice, and renal VDR is down‐regulated in AKI, but the mechanism of VDR down‐regulation is unclear. Methods: Nutritional vitamin D deficiency was induced by feeding mice a vitamin D‐deficient (VD‐D) diet. Mice were injected intraperitoneally with LPS (20 mg/kg) to establish LPS‐induced AKI. Levels of VDR and miR‐122 were measured both in vivo and in vitro. The associations between VDR and miR‐122 were analysed by dual‐luciferase reporter assays. Results: Compared with vitamin D‐sufficient (VD‐S) mice, VD‐D mice developed more severe renal injury following LPS challenge. LPS induced a dramatic decrease in VDR expression and marked induction of miR‐122 both in vivo and in vitro. Furthermore, miR‐122 hairpin inhibitor alleviated LPS‐induced VDR down‐regulation whereas miR‐122 mimic directly suppressed VDR expression in HK‐2 cells. In luciferase reporter assays, miR‐122 mimic was able to suppress luciferase activity in 293T cells co‐transfected with a luciferase reporter that contains a putative miR‐122 target site from 3′UTR of the VDR transcript, but not when this site was mutated. Moreover, miR‐122 mimic significantly blocked paricalcitol‐induced luciferase activity in 293T cells co‐transfected with a VDRE‐driven luciferase reporter, whereas miR‐122 hairpin inhibitor enhanced paricalcitol's activity to suppress PUMA and caspase 3 activation induced by LPS in HK‐2 cells. Conclusions: Collectively, these studies provide evidence that miR‐122 directly targets VDR in renal tubular cells, which strongly suggest that miR‐122 up‐regulation in the kidney under LPS challenge contributes to kidney injury by down‐regulating VDR expression. [ABSTRACT FROM AUTHOR]