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.