In the present study, we molecularly designed and synthesized multiple PI polyamides that prevent USF1 binding on the TGF-β1 promoter and examined both their effects on the promoter activity and mRNA expression of TGF-β1 in renal MCs in high-glucose conditions to determine the lead compound in vitro and the effects of injection of the lead compound on diabetic nephropathy in vivo in rats with STZ-induced diabetes mellitus. This evidence concerns the gene USF1 and diabetes mellitus.