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Fenofibrate attenuates renal lipotoxicity in uninephrectomized mice with high-fat diet-induced obesity
Barbara Bruna Abreu Castro1,2, Petrus Ferreira Reno1, Bianca Fatima Pereira1
1Universidade Federal de Juiz de Fora, Centro de Biologia da Reprodução, Núcleo de Experimentação Animal, Laboratório de Nefrologia Experimental, Juiz de Fora, MG, Brazil.
Introduction:
The objective of this study was to investigate the role of fenofibrate, a peroxisome proliferator-activated receptor-α agonist, in obesity-induced kidney damage (lipotoxicity) in mice with uninephrectomy.
Methods:
C57BL/6 mice underwent uninephrectomy and sham surgeries and were fed normocaloric or high-fat diets. After 10 weeks, obese mice were administered 0.02% fenofibrate for 10 weeks. Kidney function and morphology were evaluated, as well as levels of inflammatory and fibrotic mediators and lipid metabolism markers.
Results:
High-fat diet-fed mice developed characteristic obesity and hyperlipidemia, with subsequent renal lipid accumulation and damage, including mesangial expansion, interstitial fibrosis, inflammation, and proteinuria. These changes were greater in obese uninephrectomy mice than in obese sham mice. Fenofibrate treatment prevented hyperlipidemia and glomerular lesions, lowered lipid accumulation, ameliorated renal dysfunction, and attenuated inflammation and renal fibrosis. Furthermore, fenofibrate treatment downregulated renal tissue expression of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and local expression of fibroblast growth factor-21.
Conclusion:
Peroxisome proliferator-activated receptor-α activation by fenofibrate, with subsequent lipolysis, attenuated glomerular and tubulointerstitial lesions induced by renal lipotoxicity, thus protecting the kidneys of uninephrectomy mice from obesity-induced lesions. The study findings suggest a pathway in the pharmacological action of fenofibrate, providing insight into the mechanisms involved in kidney damage caused by obesity in kidney donors.
Insights
Fenofibrate, a PPAR-α agonist, protects kidneys from obesity-induced damage by reducing lipid accumulation and inflammation. This study highlights its potential in preventing kidney lesions in obese individuals, especially after uninephrectomy.
Area of Science:
- Nephrology
- Pharmacology
- Metabolic Diseases
Background:
- Obesity-induced kidney damage, or lipotoxicity, is a growing concern, particularly in individuals with reduced renal mass like kidney donors.
- Peroxisome proliferator-activated receptor-α (PPAR-α) agonists, such as fenofibrate, are known to modulate lipid metabolism.
Purpose of the Study:
- To investigate the protective role of fenofibrate against obesity-induced kidney damage (lipotoxicity) in a mouse model with uninephrectomy.
- To explore the underlying mechanisms involving lipid metabolism and inflammatory pathways.
Main Methods:
- C57BL/6 mice underwent uninephrectomy or sham surgery, followed by normocaloric or high-fat diets.
- Obese mice received fenofibrate treatment for 10 weeks, with subsequent evaluation of kidney function, morphology, and molecular markers.
Main Results:
- High-fat diet induced obesity, hyperlipidemia, and significant renal damage, which was exacerbated by uninephrectomy.
- Fenofibrate treatment effectively reduced hyperlipidemia, renal lipid accumulation, glomerular lesions, inflammation, and fibrosis.
- Fenofibrate downregulated key inflammatory and fibrotic mediators, including PAI-1, MCP-1, and FGF-21.
Conclusions:
- Activation of PPAR-α by fenofibrate attenuates glomerular and tubulointerstitial lesions caused by renal lipotoxicity.
- Fenofibrate demonstrates a protective effect on kidneys in uninephrectomy mice subjected to obesity-induced damage.
- The findings provide insights into fenofibrate's mechanism of action for mitigating obesity-related kidney disease, relevant for kidney donors.
