Gut-derived 4-hydroxyphenylacetic acid attenuates sepsis-induced acute kidney injury by upregulating ARC to inhibit necroptosis

Background: Studies have found that the plasma content of gut-derived 4-hydroxyphenylacetic acid (4-HPA) was significantly increased in septic patients. However, the mechanism of 4-HPA elevation during sepsis and its relationship with sepsis-induced acute kidney injury (SAKI) remain unclear. Methods: Cecal ligation and puncture (CLP) was performed in C57BL/6 mice to establish the SAKI animal model. Human renal tubular epithelial (HK-2) cells stimulated with lipopolysaccharide were used to establish the SAKI cell model. The widely targeted metabolomics was applied to analyze the renal metabolite changes after CLP. Proteomics was used to explore potential target proteins regulated by 4-HPA. The blood sample of clinical sepsis patients was collected to examine the 4-HPA content. Results: We found that renal gut-derived 4-HPA levels were significantly increased after CLP. The high permeability of intestinal barrier after sepsis contributed to the dramatic increase of renal 4-HPA. Intriguingly, we demonstrated that exogenous 4-HPA administration could further significantly reduce CLP-induced increases in serum creatinine, urea nitrogen, and cystatin C, inhibit renal pathological damage and apoptosis, and improve the survival of mice. Mechanistically, 4-HPA inhibited necroptosis in renal tubular epithelial cells by upregulating the protein expression of apoptosis repressor with caspase recruitment domain (ARC) and enhancing the interaction between ARC and receptor-interacting protein kinase 1 (RIPK1). Conclusions: The increase of gut-derived 4-HPA in the kidney after sepsis could play a protective effect in SAKI by upregulating ARC to inhibit necroptosis.