Protective Effects of Cyclosporin H Against Sepsis-Induced Acute Kidney Injury via Modulation of Fpr1 Signaling and Inhibiting Pyroptosis

Objective: This study aimed to identify potential targets and mechanisms of sepsis-associated acute kidney injury (SA-AKI) using transcriptomic analysis.

Methods: First, SA-AKI model was established by intraperitoneal LPS injection. Second, transcriptome Sequencing was performed to analyze key targets and mechanisms in SA-AKI. Finally, we investigated the therapeutic effects of the Fpr1 inhibitor Cyclosporin H on the SA-AKI model.

Results: H&E staining revealed intact renal structure in the control group, while the SA-AKI group showed structural damage, glomerular atrophy, and inflammatory cell infiltration. Serum levels of blood urea nitrogen and creatinine were significantly elevated in the SA-AKI group compared to controls (P<0.001). ELISA detection showed significantly higher TNF-α and IL-1β levels in both serum and kidney tissues of the SA-AKI group (P<0.001). Transcriptome analysis identified 209 differentially expressed genes between SA-AKI and control groups, with 194 upregulated and 15 downregulated genes. GO and KEGG analyses indicated that these genes primarily participated in leukocyte migration, phagocytosis, leukocyte chemotaxis, chemokine signaling pathways, and viral protein-cytokine interactions. qPCR confirmed significantly higher expression of Ubd, Fpr1, Fpr2, C3, B2m, and Itgam in the SA-AKI group (P<0.01). Following Cyclosporin H intervention, renal tissue damage was significantly ameliorated, with reduced renal function indicators and inflammatory markers. Additionally, TUNEL staining and transmission electron microscopy showed decreased TUNEL-positive cells, reduced mitochondrial damage, and fewer pyroptotic features after Cyclosporin H treatment. Western blot analysis demonstrated significantly decreased levels of ASC, Caspase-1, NLRP3, and IL-1β proteins after Cyclosporin H intervention (P<0.001).

Conclusion: Fpr1 may serve as a key mediator in the SA-AKI. Cyclosporin H may improve sepsis-induced kidney injury and inflammation by inhibiting Pyroptosis, providing a potential early therapeutic intervention.

Fpr1; cyclosporin H; pyroptosis; sepsis-associated acute kidney injury; transcriptomics.