Thymosin β4 Alleviates Sepsis-Associated AKI via Inhibiting MAPK Signaling Pathway

Background: Sepsis-associated acute kidney injury (SA-AKI) is prevalent in septic patients, leading to a higher mortality or progression to chronic kidney disease (CKD). Thymosin β4 (Tβ4) alleviated lipopolysaccharide (LPS)-induced liver injury and ischemic AKI via inhibiting inflammation in previous studies, whereas its role in SA-AKI remains unexplored. Therefore, we investigated whether Tβ4 protects mice against LPS-induced SA-AKI. Methods: SA-AKI murine models were established through intraperitoneally injecting LPS (10mg/kg). Exogenous Tβ4 (10mg/kg) was injected into the mice 30 min after LPS treatment. Blood and kidney tissues were collected 24h after LPS injection for further analysis. RNA sequencing was used to explore mechanism and further validated by western blotting. Results: Circulating Tβ4 levels evidently dropped in LPS-treated mice compared to the control group. Exogenous Tβ4 significantly reduced serum creatinine and blood urea nitrogen levels and ameliorated the morphologic damage in the renal tissues of LPS-treated mice. Consistently, the mRNA and protein levels of neutrophil gelatinase-associated lipocalin (NGAL) in the kidneys of SA-AKI mice were reversed by Tβ4. Moreover, the mRNA levels of pro-inflammatory cytokines, including IL-6, IL-1β, IL-18, were reduced by Tβ4 in the kidneys of SA-AKI mice. Furthermore, RNA-sequencing analysis revealed that MAPK signaling pathway might regulate both SA-AKI development and Tβ4 protection against SA-AKI. Western blotting of the murine kidneys confirmed that LPS increased the phosphorylation levels of JNK1/2, p38 MAPK and ERK1/2 protein, while Tβ4 remarkably reduced their corresponding levels. Conclusion: Tβ4 may protect against SA-AKI via inhibiting inflammation by suppression of MAPK signaling pathway. Tβ4 could be a potential drug for SA-AKI patients.