Vitamin D-VDR (vitamin D receptor) alleviates glucose metabolism reprogramming in lipopolysaccharide-induced acute kidney injury

Abstract

Background: Our previous study showed that vitamin D (VD)-vitamin D receptor (VDR) plays a nephroprotective role in lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Recently, glucose metabolism reprogramming was reported to be involved in the pathogenesis of AKI.Objective: To investigate the role of VD-VDR in glucose metabolism reprogramming in LPS-induced AKI.Methods: We established a model of LPS-induced AKI in VDR knockout (VDR-KO) mice, renal proximal tubular-specific VDR-overexpressing (VDR-OE) mice and wild-type C57BL/6 mice. In vitro, human proximal tubular epithelial cells (HK-2 cells), VDR knockout and VDR overexpression HK-2 cell lines were used.Results: Paricalcitol (an active vitamin D analog) or VDR-OE reduced lactate concentration, hexokinase activity and PDHA1 phosphorylation (a key step in inhibiting aerobic oxidation) and simultaneously ameliorated renal inflammation, apoptosis and kidney injury in LPS-induced AKI mice, which were more severe in VDR-KO mice. In in vitro experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-PDHA1). Moreover, paricalcitol activated the phosphorylation of AMP-activated protein kinase (AMPK), and an AMPK inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells.Conclusion: VD-VDR alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of PDHA1 phosphorylation via the AMPK pathway.

Adrenomedullin, transcriptionally regulated by vitamin D receptors, alleviates atherosclerosis in mice through suppressing AMPK‐mediated endothelial ferroptosis

“…NO plays an important role in angiogenesis and can promote the survival, proliferation, and migration of endothelial cells. It was reported that VD/VDR attenuated artery remodeling and endothelial dysfunction via the AMPK/eNOS in ischemia or LPS induced tissue injury 20–22 . However, the underlying mechanism is not clear.…”

“…It was reported that VD/VDR attenuated artery remodeling and endothelial dysfunction via the AMPK/ eNOS in ischemia or LPS induced tissue injury. [20][21][22] However, the underlying mechanism is not clear. Adrenomedullin (ADM) is a 52-amino acid peptide originally isolated from extracts of human pheochromocytoma belonging to the calcitonin gene-peptide superfamily, which also includes calcitonin, calcitonin gene-related peptides, and islet amyloid protein.…”