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Published on: August 19, 2020
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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.
Summary
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.
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