Cells’ survival pattern of kidney macrophages and epithelial cells in lupus nephritis is influenced by glycolysis

OBJECTIVE: Macrophages and kidney cell pyroptosis/ferroptosis could play an important role in the pathogenesis of lupus nephritis (LN). We aim to determine if glycolysis influences cell death and sustained renal inflammation in these cells. METHODS: For this purpose, we evaluated glycolysis, glutathione peroxidase and Caspase 1 activities and gene expression levels related to glycolysis, pyroptosis, ferroptosis and fatty acid oxidation in: (1) cultured human tubular cells and monocytes treated with healthy human serum or human LN serum. (2) Epithelial cells and macrophages isolated from kidneys from an in vivo murine model of LN in mice subjected to intraperitoneal administration of pristane. (3) NRK-52E tubular cells and mice Raw 264.7 macrophages treated with ovalbumin immunocomplexes (OVA-IC) to mimic LN model in vitro. RESULTS: Our results indicate that treatment of human cells and human monocytes from serum of patients with LN provoked upregulated glycolysis and enhancement of pyroptosis and ferroptosis. In the in vivo mice pristane model, the isolated renal epithelial cells and macrophages from kidneys showed an increase in expression of glycolytic and pyroptotic/ferroptotic related genes, while fatty acid oxidation was downregulated. OVA-IC administration in NRK and RAW cells promotes glycolysis upregulation and enhances pyroptosis and ferroptosis. Pharmacological inhibition of glycolysis reduces pyroptosis/ferroptosis and kidney damage in vitro and in vivo. CONCLUSION: In LN, kidney macrophages and epithelial cells have an enhanced pyroptosis/ferroptosis influenced by glycolysis since 2-deoxy-D-glucose treatment reverts these effects.