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

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-deficient mice were treated with lipopolysaccharide intraperitoneally in combination with D-galactosamine to establish a mouse model of sepsis-associated AKI. Serum inflammatory cytokines were measured using enzyme-linked immunosorbent assay. The messenger RNA (mRNA) levels of interleukin 6, tumor necrosis factor, nitric oxide synthase 2, and interleukin 1 beta were measured using quantitative reverse-transcription polymerase chain reaction. The morphological change in kidney tubule was determined by hematoxylin-and-eosin staining. The protein levels of RasGRP, extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (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 mitogen-activated protein kinase pathway, thereby reducing AKI induced by sepsis. Conclusions Our data suggest that RasGRP exacerbates lipopolysaccharide-induced acute kidney injury through regulating ERK activation, which reveals a potential therapeutic target for the treatment of sepsis-induced AKI.