Fibroblast growth factor 1 alleviates diabetic nephropathy by reducing renal lipid accumulation in diabetic kidney

Diabetic nephropathy (DN) is a major complication of diabetes, yet therapeutic strategies that specifically target its pathogenesis are still lacking.

To evaluate the therapeutic potential of fibroblast growth factor 1 (FGF1) in DN and explore its underlying mechanisms.

DN was induced in vivo using a type 2 diabetes mouse model, and in vitro using human kidney-2 (HK-2) cells treated with high glucose and palmitate acid (HGPA). Renal function, lipid accumulation and fibrosis were evaluated by urinary albumin creatinine ratio, Oil Red O staining and adipose differentiation-related protein expression, and Sirius Red staining, respectively. Oxygen consumption rate of HGPA-treated HK-2 cells with or without FGF1 was measured using the Seahorse XF Analyzer.

FGF1 treatment reduced urinary albumin excretion, ameliorated glomerular hypertrophy, attenuated renal fibrosis and inflammation, and diminished lipid accumulation in diabetic kidneys. Analysis of fatty acid metabolism revealed that cluster of differentiation 36, a key regulator of long-chain fatty acids uptake, was upregulated, while carnitine palmitoyl transferase 1A, a rate-limiting enzyme in fatty acid beta-oxidation (FAO), was downregulated in diabetic kidneys and HGPA-treated HK-2 cells. FGF1 treatment normalized the expression of both cluster of differentiation 36 and carnitine palmitoyl transferase 1A and enhanced FAO in HGPA-treated HK-2 cells. Mechanistically, FGF1 restored AMP-activated protein kinase (AMPK) activity and peroxisome proliferator-activated receptor alpha expression, both of which were suppressed in DN and HGPA-treated HK-2 cells. Notably, pharmacological inhibition of AMPK or FAO abolished the protective effect of FGF1.

FGF1 alleviates DN by inhibiting fatty acid uptake and promoting lipid catabolism via AMPK activation and FAO enhancement.