FGF-21 Protects Against Sepsis-Associated Acute Kidney Injury by Modulating Inflammation and Autophagy via the AMPK/mTOR1 Pathway.

Abstract

This preclinical/clinical study aimed to evaluate the potential protective effects of fibroblast growth factor-21 (FGF-21) against sepsis-associated acute kidney injury (S-AKI). Serum samples from patients diagnosed with sepsis and S-AKI were collected. In the cecal ligation and puncture (CLP) model of S-AKI, recombinant FGF-21 or small interference RNAs targeting FGF-21 (si-FGF-21) were given to mice. Kidney function tests and histological examination of kidney tissue from mice were performed. HK-2 renal epithelial cells and RAW264.7 macrophages exposed to lipopolysaccharides were treated with either si-FGF-21 or recombinant FGF-21. Cytokine levels (e.g., IL-6, TNF-α, IL-1β) and relative expression levels of FGF-21, IL-6, TNF-α, IL-1β, P62, ATG5, and LC3-II/I in lipopolysaccharide-stimulated macrophages of mice were measured. Serum levels of TNF-α, IL-1β, IL-6, and FGF-21 were significantly higher in S-AKI patients than in those with sepsis and healthy individuals. There were significantly higher mRNA expression and protein levels of FGF-21 in LPS-treated HK-2 cells compared to controls. FGF-21 siRNA increased TNF-α, IL-1β, and IL-6 levels compared with the control group. FGF-21 knockdown significantly increased apoptosis in HK-2 cells under LPS stimulation. FGF-21 overexpression significantly attenuated the inhibitory effect of LPS on AMPK and mTOR1 phosphorylation in HK-2 cells. Finally, the recombinant FGF-21-treated group of mice showed lower serum creatinine and BUN levels than the CLP-alone group. Our data suggest that FGF-21 has anti-inflammatory effects and restores autophagy dysfunction in S-AKI, in part by modulating the AMPK/mTOR1 signaling pathway.