Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice - 08/01/20
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Graphical abstract |
Schematic diagram of fisetin in LPS-induced septic AKI.
Fisetin modulated the activities of TLR4/Src-mediated NF-κB p65 and MAPK pathways, thus alleviating kidney inflammation and apoptosis in LPS-induced septic AKI.
Highlights |
• | Fisetin is a polyphenolic flavonoid in many fruits and vegetables. |
• | Fisetin alleviated kidney injury against LPS-induced septic AKI. |
• | Fisetin inhibited LPS-induced kidney inflammation and apoptosis. |
• | Fisetin inhibited renal Src-mediated NF-κB and MAPK signalling pathways in LPS-induced septic AKI. |
Abstract |
Background |
Sepsis is defined as end-organ dysfunction resulting from the host’s inflammatory response to infection. One of the most common sepsis-injured organs is the kidneys, resulting in acute kidney injury (AKI) that contributes to the high morbidity and mortality, especially patients in the intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported to protect against the rat of lipopolysaccharide (LPS)-induced acute lung injury. However, the effect of fisetin on septic AKI remains unknown.
Purpose |
The current study proposed to systematically investigate the renoprotective effects and the underlying mechanisms of fisetin in septic AKI mice.
Methods |
The model of septic AKI was established on male C57BL/6 J mice by a single intraperitoneal injection of LPS (10 mg/kg). Fisetin was administrated by gavage at 100 mg/kg for 3 consecutive days before LPS injection and the mice were sacrificed at 16 h after LPS injection. The serum and kidney samples were evaluated for biochemical analysis, histopathological examinations as well as inflammation and apoptosis related gene/protein expression.
Results |
Pretreatment with fisetin significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in LPS-treated mice. Consistently, LPS induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by fisetin. Meanwhile, LPS injection triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, fisetin inhibited renal expression of IL-6, IL-1β, TNF-α, HMGB1, iNOS and COX-2 to improve inflammatory response. Furthermore, fisetin effectively reduced the number of TUNEL positive apoptotic cells and suppressed apoptotic protein of Bcl-2, BAX and cleaved caspase-3 in the kidneys of LPS-induced septic AKI. Mechanistically, LPS stimulated the expression of TLR4 and the phosphorylation of NF-κB p65, MAPK (p38, ERK1/2 and JNK), Src and AKT in the injured kidneys, while fisetin notably suppressed the corresponding protein expression.
Conclusion |
Fisetin alleviated kidney inflammation and apoptosis to protect against LPS-induced septic AKI mice via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways
Le texte complet de cet article est disponible en PDF.Abbreviations : LPS, AKI, BUN, MAPKs, NGAL, KIM-1, PCR, HMGB1, iNOS, COX-2, BAX, CC3, NF-κB, JNK, ERK, Src, TLR4
Keywords : Fisetin, Sepsis, Acute kidney injury, Lipopolysaccharide, Inflammation, Apoptosis
Plan
Vol 122
Article 109772- février 2020 Retour au numéro
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