RasGRP Exacerbates Lipopolysaccharide-Induced Acute Kidney Injury Through Regulation of ERK Activation

Abstract

Background Excessive inflammatory activities are reported to be the primary cause of sepsis-induced acute kidney injury (AKI). Ras guanyl nucleotide releasing protein (RasGRP) could prevent inflammatory response. However, its role in the regulation of inflammatory response in sepsis-associated AKI remains unclear. Methods Wild-type or RasGRP1 deficiency mice were treated with lipopolysaccharides intraperitoneally in combination with D-galactosamine to establish a mouse model of sepsis-associated AKI. Serum inflammatory cytokines were measured using ELISA. The mRNA levels of Il6, Tnf, Nos2, and Il1b were measured using q-RT-PCR. The morphological change in kidney tubule was determined by hematoxylin and eosin staining. The protein levels of RasGRP, Erk1/2, and Jnk were determined using Western blot. Results RasGRP1 mRNA and protein levels were significantly increased in patients with sepsis-related AKI compared to those in healthy subjects. RasGRP knockout markedly reduced inflammatory cytokines induced by AKI in sepsis when compared with wild-type mice. Additionally, RasGRP deficiency inhibited the phosphorylation of ERK1/2 without altering Jnk expression. In conclusion, we demonstrate that RasGRP1 plays a pivotal role in sepsis-associated AKI. Downregulation of RasGRP1 could significantly inhibit inflammatory response by inhibiting the activation of ERK1/2 and MAPK pathway, thereby reducing AKI induced by sepsis. Conclusion Our data suggest that RasGRP exacerbates lipopolysaccharides-induced acute kidney injury through regulating ERKs activation, which reveals a potential therapeutic target for the treatment of sepsis-induced AKI.