Methionine sulfoxide reductase A deficiency aggravated ferroptosis in LPS-induced acute kidney injury by inhibiting the AMPK/NRF2 axis and activating the CaMKII/HIF-1α pathway.

Methionine sulfoxide reductase A (MsrA) is an important antioxidant enzyme that is present in various tissues and play a crucial role in many pathological processes. However, the role of MsrA in acute kidney injury (AKI) requires further exploration. Here, we aimed to explore whether MsrA is involved in sepsis-associated AKI and the underlying mechanisms. In the present study, AKI was induced by lipopolysaccharide (LPS) in WT mice and MsrA knockout mice. The role of MsrA in LPS-induced injury in the human renal proximal tubule epithelial cell line HK-2 was also examined by MsrA knockdown. MsrA deficiency exacerbated LPS-induced kidney damage in vivo. In addition, MsrA deficiency and silencing intensified iron overload, lipid peroxidation and ferroptosis in LPS-stimulated renal tubular cells. The mechanistic study revealed that MsrA knockout or knockdown led to the oxidation of calcium/calmodulin-dependent protein kinase II (CaMKII) at methionine 281/282, resulting in sustained activation of CaMKII, which upregulated iron metabolism-related proteins such as transferrin receptor 1 (TFR1) by promoting phosphorylation and nuclear translocation of hypoxia-inducible factor-1α (HIF-1α) and induced abnormal iron metabolism. Meanwhile, CaMKII activation downregulated the expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) by inhibiting the activity of AMP-activated protein kinase (AMPK) and phosphorylation of nuclear factor erythroid 2-related factor 2 (NRF2), resulting in lipid peroxidation. Consequently, LPS-induced ferroptosis was exacerbated. Our study is the first to reveal that MsrA deficiency intensifies LPS-induced ferroptosis through CaMKII activation in renal tubular cells. There are two major mechanisms: one is the promotion of lipid peroxidation by inhibiting the AMPK/NRF2 axis, and the other is abnormal iron metabolism by activating the HIF-1α/TFR1 pathway. MsrA may be a potential therapeutic target for organ and cell damage induced by ferroptosis.