Abstract
Sepsis-associated acute kidney injury (AKI) has high morbidity and mortality, but without cause-specific treatment. Erythropoietin derived Helix B surface peptide (HBSP) alleviates AKI, whereas its underlying mechanisms remain to be further explored. Here, the effects of HBSP on pyroptosis, apoptosis, macrophage polarization and repair were investigated in lipopolysaccharide (LPS)-induced AKI mouse model and cultured kidney epithelial cells. Systemic inflammation, compromised renal function and histology were demonstrated in LPS-treated mice, with upregulated pyroptotic and apoptotic key proteins in the kidneys including GSDMD-N, cleaved IL-1β, IL-18 and caspase-3. These proteins were localized in tubular areas and colocalized with aquaporin-1 (AQP1), with increased F4/80+ M1 macrophages. However, HBSP mitigated pyroptosis, apoptosis and inflammation, and promoted macrophage M2 polarization. In addition, HMGB1 and erythropoietin receptor (EPOR) were increased by LPS and decreased by HBSP, both of which were positively correlated with pyroptotic and apoptotic proteins. Moreover, HBSP reduced TNF-α and IL-6 mRNA levels, as well as pyroptosis and apoptosis in LPS-stimulated TCMK-1 cells. In conclusion, HBSP inhibited tubular pyroptosis and apoptosis, EPOR expression, promoted macrophage M2 polarization, and protected against LPS-induced AKI. These findings provide new mechanistic insights into the renoprotection of HBSP, and facilitate its potential for clinical applications and therapeutic strategies in sepsis-associated AKI.