RPS3 Aggravates Sepsis-Induced Acute Kidney Injury Through Activating NF-kappaB Mediated Renal Inflammatory Responses

Excessive inflammatory responses represent one of the primary causes of sepsis- associated acute kidney injury (S-AKI). The activation of the nuclear factor-kappa B (NF-kappaB) signaling pathway plays a critical role in the pathogenesis and progression of S-AKI. Previous studies have demonstrated that ribosomal protein S3 (RPS3) serves as a pivotal regulator of the NF-kappaB pathway; however, its specific biological functions in the context of S-AKI remain to be fully elucidated. This study aims to elucidate the regulatory mechanisms of RPS3 in S-AKI-associated inflammation and to explore the underlying molecular pathways. First, we conducted an analysis of RPS3 level in urine and TNF-alpha level in serum from S-AKI patients recruited at our hospital. Second, we established a murine model of S-AKI by intraperitoneal injection of LPS, followed by the evaluation of renal function, inflammatory response, RPS3 expression, and NF-kappaB activation in renal tissues. Finally, we explored the regulatory role and underlying mechanism of RPS3 in the LPS-induced inflammatory response in HK-2 cells through RPS3 knockdown and the introduction of an NF-kappaB agonist. The results demonstrated that urinary RPS3 and serum TNF-alpha levels were significantly elevated in patients with S-AKI, with a positive correlation observed between these two parameters. In LPS-induced S-AKI mice, renal function was impaired, accompanied by a robust inflammatory response, increased RPS3 protein expression, and enhanced NF-kappaB activation in kidney tissue. Knockdown of RPS3 in HK-2 cells mitigated LPS-induced the inflammatory response and suppressed NF-kappaB activation. However, the effects of RPS3 silencing were partially reversed upon intervention with an NF-kappaB agonist. Collectively, these findings indicate that RPS3 plays a critical role in the inflammatory response of S-AKI via activation of the NF-kappaB signaling pathway, suggesting its potential as a novel therapeutic target for S-AKI. Key words Sepsis-associated acute kidney injury " Inflammatory response " Ribosomal protein S3 " Nuclear factor-kappa B.