Key module genes in proximal tubular cells drive microenvironmental chronic inflammation and fibrosis in diabetic kidney disease: A single-cell transcriptomic study

作者：Zhou W, Chen Z, Ying G, Liu L, Xiao W, Liu J, Xia M, Zhang Q, He X · 发表于：Biochimica et biophysica acta. Molecular basis of disease · 年份：2026 · DOI：10.1016/j.bbadis.2026.168326 · 研究领域：Kidney Tubules, Proximal、Diabetic Nephropathies、Inflammation、Transcriptome、Fibrosis、Humans、Single-Cell Gene Expression Analysis、Single-Cell Analysis、Epithelial Cells、Gene Expression Profiling、Animals、Gene Expression Regulation

Diabetic kidney disease (DKD) is one of the most severe microvascular complications of diabetes, with proximal tubular (PT) epithelial cells playing a pivotal role in its progression, yet the underlying dynamic molecular mechanisms remain unclear. In this study, single-cell transcriptomic dataset GSE183276 and bulk RNA-seq dataset GSE30122 were integrated to systematically analyze the heterogeneity and functional alterations of PT epithelial cells in DKD. PT epithelial cells were classified into three subpopulations: PT-Homeostatic, PT-Transitional and PT-Stressed. In DKD, the PT-Homeostatic subpopulation decreased markedly, whereas PT-Transitional and PT-Stressed subpopulations increased significantly. Functional enrichment analyses revealed that PT-Homeostatic cells mainly participated in amino acid and fatty acid metabolism; PT-Transitional cells were enriched in wound repair, Wnt signaling and oxidative stress response; PT-Stressed cells were associated with fibroblast proliferation, anti-apoptosis and chemotaxis regulation. Pseudotime analysis indicated that PTECs gradually shift from a homeostatic to a stressed phenotype during DKD progression. Eight core downregulated genes were further screened, among which HPGD and G6PC were specifically highly expressed in PT-Homeostatic cells and significantly downregulated in DKD. In vitro experiments demonstrated that high glucose repressed transcription factor RXRA expression to further reduce G6PC transcription. RXRA overexpres...