Tier 3 — preclinical

Natural flavonol fisetin attenuated hyperuricemic nephropathy via inhibiting IL-6/JAK2/STAT3 and TGF-β/SMAD3 signaling

Ren Q, Tao S, Guo F, Wang B, Yang L, Ma L, Fu P
Phytomedicine 2021 Volume 87, article 153552

Bibliography

PubMed
PMID 33994251
DOI
10.1016/j.phymed.2021.153552
Funding
Key Research & Development Program of Sichuan Province (2021YFQ0027).
Competing interests
All authors have read the journal's policy on disclosure of potential conflicts of interest and have none to declare.

Study snapshot

DesignIn vivo hyperuricemic nephropathy mouse model (both simultaneous and delayed-treatment protocols) with renal function, histology and RNA-seq/RT-PCR/western blot analysis, plus in vitro uric-acid-stimulated TCMK-1 mouse tubular epithelial cell experiments.
ModelMale C57BL/6J mice with hyperuricemic nephropathy induced by adenine (160 mg/kg) plus potassium oxonate (2400 mg/kg); mouse kidney tubular epithelial cell line TCMK-1.
Sample5 groups of 6 mice each (control, HN model, allopurinol positive control, fisetin 50 mg/kg, fisetin 100 mg/kg); in vitro experiments performed in triplicate.
InterventionOral fisetin 50 or 100 mg/kg given either simultaneously with hyperuricemic nephropathy induction or after HN was already established (delayed treatment, additional 2 weeks); allopurinol 10 mg/kg as positive control; in vitro fisetin 5-40 micromolar with uric acid 0.8 mM.
DurationSimultaneous-treatment protocol over 4 weeks; delayed-treatment protocol extended to a 28-day HN induction period followed by a further 2 weeks of fisetin dosing.
EndpointsSerum and urinary uric acid, creatinine, BUN and urinary albumin-to-creatinine ratio; Renal histopathology (PAS and Masson's trichrome staining, tubular injury and fibrotic scores); Urate transporter expression (URAT1, OAT1, OAT3, ABCG2); Pro-inflammatory cytokines (TNF-alpha, IL-6, MCP-1) and fibrosis markers (alpha-SMA, collagen I, fibronectin); STAT3 and TGF-beta/Smad3 signalling activation; Kidney transcriptome (RNA-seq) changes

What the study showed, in plain terms

This West China Hospital nephrology group tested whether fisetin can protect the kidneys in a mouse model of hyperuricemic nephropathy - kidney damage caused by chronically high uric acid, a condition relevant to gout and chronic kidney disease.

Fisetin (particularly at 100 mg/kg) lowered blood uric acid nearly to normal levels, improved kidney function markers (creatinine, BUN, urinary albumin-to-creatinine ratio), and preserved kidney tissue architecture on biopsy, working in part by restoring the normal balance of urate transporter proteins (URAT1, OAT1, OAT3, ABCG2) that control how much uric acid the kidney reabsorbs versus excretes.

Fisetin also reduced kidney inflammation (lower TNF-alpha, IL-6, MCP-1) and fibrosis (scarring) markers, and RNA sequencing of kidney tissue pointed to two specific signalling pathways, IL-6/JAK2/STAT3 and TGF-beta/Smad3, as the mechanisms fisetin was blocking - confirmed directly in uric-acid-stimulated kidney cells in the dish.

A clinically encouraging detail: fisetin worked whether it was started at the same time as kidney injury or given afterward, once hyperuricemic kidney disease was already established, suggesting a treatment window rather than only a prevention window.

As with the companion fisetin kidney papers in this Data Center, the effective doses were oral but higher than typical human supplement doses, and the model is a chemically-induced mouse hyperuricemia rather than naturally occurring human gout or CKD, so direct human dose translation is not established.

Key findings

  • Fisetin (100 mg/kg) lowered serum uric acid nearly to control levels in hyperuricemic mice
  • Fisetin improved serum creatinine, BUN and urinary albumin-to-creatinine ratio
  • Fisetin restored expression of the urate transporters URAT1, OAT1, OAT3 and ABCG2
  • Fisetin reduced renal TNF-alpha, IL-6 and MCP-1 and improved tubulointerstitial fibrosis
  • Fisetin inhibited IL-6/JAK2/STAT3 and TGF-beta/Smad3 signalling in kidney tissue and uric-acid-stimulated cells
  • Delayed fisetin treatment (started after HN was established) still improved renal function and fibrosis

What this study can and cannot tell us

The adenine/potassium-oxonate chemical model of hyperuricemic nephropathy differs mechanistically from naturally occurring human gout, chronic kidney disease or uric-acid nephrolithiasis.

Other known urate excretion transporters (such as GLUT9 and MRP4) were not examined, so the full transporter mechanism remains incompletely characterised.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology