Early Renal microRNA Signatures of Septic Acute Kidney Injury in Neonatal Pigs

Acute kidney injury (AKI) is a major complication of neonatal sepsis, yet the early molecular events underlying sepsis-associated AKI (SA-AKI) in the maturing kidney remain poorly defined. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that may contribute to the inflammatory, stress, and remodeling responses associated with SA-AKI. We profiled renal miRNA expression in neonatal pigs 12 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP increased plasma lactate, C-reactive protein, and procalcitonin and was accompanied by evidence of kidney injury, including increased plasma creatinine, symmetric dimethylarginine, and urinary neutrophil gelatinase-associated lipocalin. NanoString profiling of 803 endogenous miRNAs, followed by sequence-based porcine annotation, identified a distinct renal miRNA signature that separated CLP and sham kidneys by principal component analysis. Differential expression analysis identified 14 upregulated and 5 downregulated miRNAs in septic kidneys. Several differentially expressed miRNAs were associated with biomarkers of systemic inflammation and kidney injury. Integrating miRNA profiles with target-gene expression revealed inverse miRNA-mRNA relationships involving PTGS2, FOS, AKT1, KLF6, NF-κB1, and SMAD2, with ssc-miR-374b-5p showing the broadest inverse relationship with these upregulated targets. Pathway enrichment analysis further implicated HIF-1, TGF-β, FoxO, autophagy/mitophagy, cell-cycle regulation, focal adhesion, and cellular senescence. Collectively, these findings demonstrate rapid remodeling of the renal miRNA landscape during early polymicrobial sepsis and identify candidate miRNA-mRNA regulatory networks that may contribute to the early pathogenesis of neonatal SA-AKI.