In this study, we first verified that ARAP1 knockdown can alleviate ECM accumulation and renal dysfunction and glomerulosclerosis in diabetic db/db mice as well as in GMCs exposed to high glucose through reducing aberrant glycolysis via decreasing HIF-1α nuclear accumulation, possibly associated with reduced expression and nucleus translocation of dimer PKM2 accompanied by restoring tetramer formation led by breaking the EGFR persistent transactivation. The gene discussed is EGFR; the disease is glomerulosclerosis.