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Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice
1Department of Internal Medicine, Wonkwang University, Gunpo 570–479, South Korea.
Abstract:
Despite the emerging importance of fibroblast growth factor 21 (FGF21) as a metabolic hormone regulating energy balance, its direct effects on renal function remain unexplored. FGF21 was injected ip daily for 12 weeks into db/db mice. Compared with control vehicle injection, FGF21 treatment significantly improved lipid profiles and insulin resistance and resulted in significantly higher serum adiponectin levels. In contrast, serum insulin and 8-isoprostane levels were significantly decreased. Interestingly, FGF21 and its receptor components in the kidneys were found to be significantly up-regulated in db/db mice, which suggests an FGF21-resistant state. FGF21 treatment significantly down-regulated FGF21 receptor components and activated ERK phosphorylation. FGF21 administration also markedly decreased urinary albumin excretion and mesangial expansion and suppressed profibrotic molecule synthesis. Furthermore, FGF21 improved renal lipid metabolism and oxidative stress injury. In cultured renal cells, FGF21 was mainly expressed in mesangial cells, and knockdown of FGF21 expression by stealth small interfering RNA further aggravated high-glucose-induced profibrotic cytokine synthesis in mesangial cells. Our results suggest that FGF21 improves insulin resistance and protects against renal injury through both improvement of systemic metabolic alterations and antifibrotic effects in type 2 diabetic nephropathy. Targeting FGF21 could therefore provide a potential candidate approach for a therapeutic strategy in type 2 diabetic nephropathy.
Insights
Fibroblast growth factor 21 (FGF21) treatment improved kidney function in diabetic mice by enhancing insulin sensitivity and reducing kidney damage. FGF21 also demonstrated antifibrotic effects, suggesting its therapeutic potential for diabetic nephropathy.
Area of Science:
- Endocrinology
- Nephrology
- Metabolic Research
Background:
- Fibroblast growth factor 21 (FGF21) is a key metabolic hormone.
- Its role in renal function, particularly in diabetic nephropathy, is largely unknown.
- Diabetic mice exhibit increased FGF21 and receptor expression, indicating potential resistance.
Purpose of the Study:
- To investigate the effects of FGF21 on renal function in a mouse model of type 2 diabetes.
- To explore the underlying mechanisms of FGF21's action on kidney injury and metabolic alterations.
Main Methods:
- Daily intraperitoneal injections of FGF21 for 12 weeks in db/db mice.
- Analysis of serum markers, renal histology, gene expression, and cell culture studies.
- Utilized stealth small interfering RNA for gene knockdown experiments.
Main Results:
- FGF21 treatment improved lipid profiles, insulin resistance, and adiponectin levels.
- Reduced serum insulin and oxidative stress markers (8-isoprostane).
- Decreased urinary albumin excretion, mesangial expansion, and profibrotic molecule synthesis, while improving renal lipid metabolism.
Conclusions:
- FGF21 ameliorates type 2 diabetic nephropathy by improving systemic metabolic health and exerting direct antifibrotic effects on the kidneys.
- FGF21 may represent a promising therapeutic target for managing diabetic kidney disease.
