AUTHOR=Dai Qing , Zhang Hao , Tang Shiqi , Wu Xueqin , Wang Jianwen , Yi Bin , Liu Jishi , Li Zhi , Liao Qin , Li Aimei , Liu Yan , Zhang Wei 

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

JOURNAL=Frontiers in Physiology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1083643

DOI=10.3389/fphys.2023.1083643

ISSN=1664-042X

ABSTRACT=<p><bold>Background:</bold> Our previous study showed that vitamin D (VD)-vitamin D receptor (<italic>VDR</italic>) 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.</p><p><bold>Objective:</bold> To investigate the role of VD-<italic>VDR</italic> in glucose metabolism reprogramming in LPS-induced AKI.</p><p><bold>Methods:</bold> We established a model of LPS-induced AKI in <italic>VDR</italic> knockout (<italic>VDR</italic>-KO) mice, renal proximal tubular-specific <italic>VDR</italic>-overexpressing (<italic>VDR</italic>-OE) mice and wild-type C57BL/6 mice. <italic>In vitro</italic>, human proximal tubular epithelial cells (HK-2 cells), <italic>VDR</italic> knockout and <italic>VDR</italic> overexpression HK-2 cell lines were used.</p><p><bold>Results:</bold> Paricalcitol (an active vitamin D analog) or <italic>VDR</italic>-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 <italic>VDR</italic>-KO mice. In <italic>in vitro</italic> experiments, glucose metabolism reprogramming, inflammation and apoptosis induced by LPS were alleviated by treatment with paricalcitol or dichloroacetate (DCA, an inhibitor of p-<italic>PDHA1</italic>). Moreover, paricalcitol activated the phosphorylation of <italic>AMP</italic>-activated protein kinase (<italic>AMPK</italic>), and an <italic>AMPK</italic> inhibitor partially abolished the protective effect of paricalcitol in LPS-treated HK-2 cells.</p><p><bold>Conclusion:</bold> VD-<italic>VDR</italic> alleviated LPS-induced metabolic reprogramming in the kidneys of AKI mice, which may be attributed to the inactivation of <italic>PDHA1</italic> phosphorylation <italic>via</italic> the <italic>AMPK</italic> pathway.</p>