Hypoxia has long been considered to play an active role in the progression of fibrosis in chronic kidney disease, but its specific mechanism is not fully understood. The stimulator of interferon genes (STING) has been a research hotspot in the fields of tumor, immunity, and infection in recent years, and its role in immune and inflammatory responses related to kidney disease has gradually attracted attention. This study mainly explores the role and mechanism of STING in hypoxia-related renal fibrosis. To address this issue, we stimulated human proximal tubular epithelial (HK-2) cells with hypoxia for 48 h to construct cell models. Meanwhile, C57BL/6J male mice were used to establish a renal fibrosis model induced by renal ischemia-reperfusion injury (IRI). In our present study, we found that the GMP-AMP synthase (cGAS)-STING signaling pathway can promote the progression of renal fibrosis after hypoxic exposure, and this effect is closely related to 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3)-mediated glycolysis. Furthermore, inhibition of both STING and its downstream interferon regulatory factor 3 (IRF3) reversed elevated PFKFB3 expression, thereby attenuating hypoxia-induced renal fibrosis. Taken together, our data suggest that the cGAS-STING-IRF3-PFKFB3 signaling pathway activated under hypoxia may provide new ideas and targets for the treatment of early renal fibrosis.
Keywords: Chronic kidney disease; Glycolysis; PFKFB3; Renal fibrosis; STING.
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