Overexpression of FTO ameliorates chronic glomerulonephritis by inhibiting glycolysis in glomerular mesangial cells associated with ADPGK m

This study aims to investigate the inhibitory effect of Fat mass and obesity-associated protein (FTO) overexpression on glycolysis in glomerular mesangial cells (GMCs) and its potential therapeutic impact on chronic glomerulonephritis (CGN). An adeno-associated virus (AAV9-FTO) was constructed to explore the protective role of FTO overexpression in CGN mice in vivo. Renal tissue pathology was assessed through haematoxylin and eosin (HE) staining, Masson's trichrome staining, and TUNEL staining. The expression of proliferation markers were analyzed by Western blot. GMCs proliferation was evaluated via EdU assay, and m⁶A modification of ADP Dependent Glucokinase (ADPGK) was quantified using methylated RNA immunoprecipitation followed by qPCR (MeRIP-qPCR). The impact of FTO overexpression on ADPGK mRNA stability was assessed through Actinomycin D assay. Additionally, real-time quantitative PCR (RT-qPCR) was used to assess ADPGK mRNA expression before and after mutation of the m⁶A site. Tissue staining results demonstrated that FTO overexpression ameliorates renal pathological progression in CGN mice. Both in vivo and in vitro experiments confirmed that FTO overexpression can reduce the expression levels of proliferation markers and also inhibit the expression of glycolysis markers. Mechanistic studies revealed that FTO overexpression suppresses the glycolytic process by downregulating ADPGK expression, thereby inhibiting abnormal proliferation of GMCs. Collectively, these findings demonstrate that FTO overexpression ameliorates CGN by inhibiting glycolysis in GMCs.