Tier 3 — preclinical

Flavonoid fisetin alleviates kidney inflammation and apoptosis via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways in septic AKI mice

Ren Q, Guo F, Tao S, Huang R, Ma L, Fu P
Biomedicine & Pharmacotherapy 2019 122:109772

Bibliography

PubMed
PMID 31918290
DOI
10.1016/j.biopha.2019.109772
Funding
Not explicitly stated in the reviewed sections; conducted at the Division of Nephrology and National Clinical Research Center for Geriatrics, Kidney Research Institute, West China Hospital of Sichuan University.
Competing interests
Not stated in the reviewed sections.

Study snapshot

DesignLPS (10 mg/kg, single intraperitoneal injection)-induced septic acute kidney injury (AKI) in mice, with fisetin pretreatment (100 mg/kg/day by gavage for 3 days before LPS), assessing renal function, histopathology, inflammatory cytokines, apoptosis markers and Src/NF-κB p65/MAPK signalling.
ModelMale C57BL/6J mice, LPS-induced septic acute kidney injury model.
SampleGroup-level comparison (control, fisetin-alone, LPS-alone, LPS+fisetin); per-group animal count not stated in reviewed sections.
InterventionFisetin 100 mg/kg/day by oral gavage for 3 consecutive days prior to LPS injection.
DurationMice sacrificed 16 hours after LPS injection, following 3 days of fisetin pretreatment.
EndpointsSerum creatinine and blood urea nitrogen; Renal histopathology score, NGAL and KIM-1 injury markers; Renal IL-6, IL-1beta, TNF-alpha, HMGB1, iNOS, COX-2 expression; TUNEL-positive apoptotic cells; Bcl-2, BAX, cleaved caspase-3; TLR4 expression and phosphorylation of NF-κB p65, MAPK (p38, ERK1/2, JNK), Src and Akt

What the study showed, in plain terms

Sepsis frequently damages the kidneys, and acute kidney injury from sepsis carries high mortality in intensive care. This study tested whether fisetin could protect the kidneys in a mouse model of sepsis-induced kidney injury.

Researchers pretreated mice with oral fisetin for three days before triggering septic kidney injury with a bacterial toxin (LPS), then measured kidney function, tissue damage and the underlying inflammatory signalling.

Fisetin pretreatment reduced the rise in creatinine and blood urea nitrogen, lessened kidney tissue damage and injury-marker levels (NGAL, KIM-1), lowered inflammatory cytokines (IL-6, IL-1beta, TNF-alpha) and apoptotic cell death in the kidney, and suppressed the Src-mediated NF-κB p65 and MAPK signalling pathways that LPS had activated.

Bottom line: as an ICU-relevant preclinical finding, this suggests fisetin has renoprotective potential in sepsis-associated acute kidney injury in mice — but it's a prevention (pretreatment) design in a single LPS-injection model, not a treatment-after-onset design, and has not been tested in critically ill patients.

Key findings

Fisetin pretreatment (100 mg/kg/day by gavage for 3 days) reduced LPS-induced elevations in serum creatinine and BUN, attenuated renal histopathological injury and NGAL/KIM-1 markers, lowered renal IL-6, IL-1beta, TNF-alpha, HMGB1, iNOS and COX-2, reduced apoptotic cell death (TUNEL, cleaved caspase-3), and suppressed LPS-induced TLR4 expression and phosphorylation of Src, NF-κB p65, and MAPK (p38, ERK1/2, JNK) in the kidneys of septic AKI mice.

What this study can and cannot tell us

Single-dose LPS injection model is a widely used but imperfect proxy for clinical sepsis, which typically involves live pathogens and a more prolonged course. Fisetin was given as pretreatment before the septic insult, not as treatment after AKI was established, limiting direct relevance to real-world ICU timing. No human data.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology