Abstract
BackgroundFibroblast growth factor 21 (FGF21) is an endocrine-acting hormone that has the potential to treat diabetic nephropathy. However, development of FGF21 into a therapeutic has been hindered due to its low intrinsic bio-stability. In our previous study, we have developed a recombinant human FGF21 (rhFGF21) variant by site-directed mutagenesis and solid-phase PEGylation, which retained its biological function. The aim of this study is to elucidate whether the therapeutic effect of PEGylated rhFGF21 (PEG-rhFGF21) on diabetic nephropathy in DIO (diet induced obesity) mice is more significant than rhFGF21 in vivo.ResultsAfter administration with rhFGF21 and PEG-rhFGF21 for 2 months, biochemical data and histological examination showed that PEG-rhFGF21 significantly lowered lipid levels in the kidney, decreased urine albumin/creatinine ratio (ACR) and improved mesangial expansion, demonstrating that PEG-rhFGF21 was more efficacious in ameliorating functional and morphological abnormalities induced by diabetic nephropathy in db/db and DIO mice.ConclusionsOur findings suggest that PEG-rhFGF21 treatment is more effective in treating diabetic nephropathy than rhFGF21, through enhancements of systemic metabolic alterations and anti-inflammatory mechanisms. These findings help provide a theoretical basis to develop more long-acting and efficacious protein drugs for diabetic nephropathy.
Highlights
Fibroblast growth factor 21 (FGF21) is an endocrine-acting hormone that has the potential to treat diabetic nephropathy
We have evaluated the efficacy of this engineered Polyethylene glycol (PEG)-recombinant human FGF21 (rhFGF21) for treatment of diabetic nephropathy in db/db and diet-induced obesity (DIO) mice
The hypoglycemic effects of PEG-rhFGF21 and rhFGF21 in DIO mice The metabolic effects of rhFGF21 have been previously evaluated by other groups using leptindeficient and high-fat diet-induced obesity (DIO) models [23,24,25,26]
Summary
Fibroblast growth factor 21 (FGF21) is an endocrine-acting hormone that has the potential to treat diabetic nephropathy. Fibroblast growth factors (FGFs) carry out their pleiotropic functions in development, transformation, tissue homeostasis and metabolism [1,2,3]. In 2005, Alexei et al firstly confirmed that FGF21 as a potent metabolic regulator can lower the levels of blood glucose and triglyceride when therapeutically administered to diabetic rodents [7]. Recent clinical trials of an FGF21 variant did not significantly reduce the glucose level, probably due to its short serum half-life in vivo [13]. Polyethylene glycol modification (PEGylation) is regarded as one of the most successful strategies to improve pharmacokinetic properties of protein drugs by increasing their in-vivo circulation half-life, which implies
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