The global proteome and phosphoproteome landscape of sepsis-induced kidney injury

Sepsis-induced acute kidney injury (S-AKI) is the most common complication in hospitalized and critically ill patients, highlighted by a rapid decline of kidney function occurring a few hours or days after sepsis onset. Systemic inflammation elicited by microbial infections is believed to lead to kidney damage under immunocompromised conditions. However, while AKI has been recognized as a disease with long-term sequelae, partly due to the associated higher risk of chronic kidney disease (CKD), the understanding of kidney pathophysiology at the molecular level and the global view of dynamic regulations in situ after S-AKI, including transition to CKD, remains limited. Existing studies of S-AKI mainly focus on deriving sepsis biomarkers from body fluids. In the present study, we constructed a mid-severity septic murine model using cecal ligation and puncture (CLP), and examined the temporal changes to the kidney proteome and phosphoproteome at day 2 and day 7 after CLP surgery, corresponding to S-AKI and the transition to CKD, respectively by employing an ultrafast and economical filter-based sample processing method combined with the label-free quantitation approach. Collectively, we identified 2,119 proteins and 2,950 phosphosites through multi-proteomics analyses. Here we denote the pathways that are specifically responsive to S-AKI and its transition to CKD, which include regulation of cell metabolism regulation, oxidative stress, and energy consumption in the diseased kidneys. Our data can serve as an enriched resource for the identification of mechanisms and biomarkers for sepsis-induced kidney diseases. * AKI : Acute kidney injury BAD : Bcl2-associated agonist of cell death protein CKD : Chronic kidney disease CLP : Cecal ligation and puncture DAMPs : Damage-associated molecular patterns ELISA : Enzyme-linked immunosorbent assay ESCRT : Endosomal sorting complexes required for transport FADD : FAS-associated death domain protein FC : Fold change FDR : False discovery rate GO : Gene Ontology Gsdmd : Gasdermin D ICU : Intensive care unit KEGG : Kyoto Encyclopedia of Genes and Genomes LFQ : Label-free quantitation NGAL : Neutrophil gelatinase-associated lipocalin protein PAMPs : Pathogen-associated molecular patterns PAS : Periodic acid-Schiff PCA : Principle component analysis S-AKI : Sepsis-induced acute kidney injury SLC : Solute carrier proteins STrap : Suspension Trapping TLRs : Toll-like receptors