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Podocyte FFAR4 deficiency aggravated glomerular diseases and aging

Ting Yin1, Letian Yang2, Lei Tang2

  • 1Department of Nephrology, Institute of Kidney Diseases, West China Hospital of Sichuan University, Chengdu 610041, China; Department of Pathology, Institute of Clinical Pathology, West China Hospital of Sichuan University, Chengdu 610041, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|June 1, 2025
PubMed

Insights

Free fatty acid receptor 4 (FFAR4) protects podocytes from injury and aging by activating CaMKKβ-AMPK signaling. Restoring FFAR4 function offers a promising therapeutic strategy for kidney diseases.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Gerontology

Background:

  • Podocyte injury drives glomerular disease progression and aging.
  • Current therapies for kidney outcomes are limited, with poorly defined causative pathways.
  • Free fatty acid receptor 4 (FFAR4) agonists previously showed promise in diabetic nephropathy.

Purpose of the Study:

  • To investigate the role of podocyte FFAR4 in glomerular diseases and aging.
  • To explore FFAR4 as a potential therapeutic target for kidney protection.

Main Methods:

  • Assessed glomerular FFAR4 expression in human patients and mouse models (focal segmental glomerulosclerosis, diabetic kidney disease).
  • Utilized systemic and podocyte-specific FFAR4 deletion models.
  • Administered FFAR4 agonist TUG891 and fish oil in adriamycin-induced nephropathy, diabetic, and aging mouse models.
  • Investigated FFAR4's mechanistic effects on cellular senescence and lipid metabolism via CaMKKβ-AMPK signaling.

Main Results:

  • Glomerular FFAR4 expression was decreased in patients with glomerular diseases and correlated with kidney function decline.
  • FFAR4 deficiency exacerbated glomerular damage in mouse models.
  • FFAR4 agonism (TUG891, fish oil) alleviated kidney injury in various disease models.
  • FFAR4 reduction induced podocyte senescence and lipid metabolism disorder.
  • FFAR4 activation via CaMKKβ-AMPK signaling demonstrated anti-senescent and anti-lipotoxic effects.

Conclusions:

  • FFAR4 plays a critical protective role in podocytes against injury and aging.
  • FFAR4 dysfunction contributes to cellular senescence and lipid metabolism abnormalities in kidney disease.
  • Targeting FFAR4 offers a novel therapeutic avenue for glomerular diseases and age-related kidney decline.
Keywords:
agingcellular senescencefish oilfree fatty acid receptor 4glomerular diseaseslipid metabolismpodocyte

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