The major findings of this study include the following: (i) we observed that NEU1 was significantly elevated in TEC of fibrotic kidneys from human and mice; (ii) we characterized NEU1 as a promotor of renal fibrosis using genetically-engineered mice and epithelial cellular models; (iii) mechanistically, NEU1 interacted with ALK5 at the amino acid 160–200 region and enhanced the ALK5-SMAD2/3 signaling pathway; and (iv) salvianolic acid B screened from natural compounds showed high affinity to human NEU1 and effectively prevented renal injury. This evidence concerns the gene SMAD2 and renal fibrosis.