Up to 40% of diabetic patients have a chance of losing normal kidney function and may develop diabetic kidney disease (DKD). Multiple genome-wide association studies (GWAS) have identified thousands of variants associated with kidney functions; however, since most of them are in non-coding regions, GWAS by themselves are unable to identify an underlying mechanism of variants. To overcome this issue, we performed a comparative analysis of adult human kidneys between 6 normal and 4 DKD patients through the epigenetic profiling of single nucleus chromatin accessibility (snATAC-seq) and three-dimensional chromatin architecture (Hi-C) on the paired sample. We mapped cell-type-specific epigenetic changes and highlighted proximal tubule (PT) as a driver cell type for the pathogenesis of DKD. PT cells from DKD kidneys were characterized by an increased response to oxidative stress and profibrotic gene regulatory network. We found BACH1 as a novel transcription factor leading to proximal tubulopathy in DKD, which induces proinflammatory genes such as TNF-a. We expect our work can help identify novel genes and cellular pathways, involved in impaired kidney functions underlying DKD and offer new clinical insights.