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

Abstract

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.AbbreviationsAKIAcute kidney injuryBADBcl2-associated agonist of cell death proteinCKDChronic kidney diseaseCLPCecal ligation and punctureDAMPsDamage-associated molecular patternsELISAEnzyme-linked immunosorbent assayESCRTEndosomal sorting complexes required for transportFADDFAS-associated death domain proteinFCFold changeFDRFalse discovery rateGOGene OntologyGsdmdGasdermin DICUIntensive care unitKEGGKyoto Encyclopedia of Genes and GenomesLFQLabel-free quantitationNGALNeutrophil gelatinase-associated lipocalin proteinPAMPsPathogen-associated molecular patternsPASPeriodic acid-SchiffPCAPrinciple component analysisS-AKISepsis-induced acute kidney injurySLCSolute carrier proteinsSTrapSuspension TrappingTLRsToll-like receptorsView Full Text