Renal Tubular Epithelial Cells Senescence Induced by 1-Aminopyrene Activates Fibroblast via BRD4 Driven Senescence-Associated Secretory Phenotype Signaling.

Epidemiological evidence links environmental pollution to chronic kidney disease (CKD). However, the molecular mechanisms by which diesel-derived pollutants trigger and sustain renal fibrosis are still unclear. In this study, we show that 1-aminopyrene (1-AP), a metabolite of diesel exhaust, leads to genomic instability and renal tubular epithelial cell (RTEC) senescence. Exposure of RTECs to sub-cytotoxic concentrations of 1-AP caused persistent DNA damage, as shown by comet assay and γ-H2AX foci. Sustained DNA damage activated the p21-mediated cellular senescence, followed by induction of SASP factors (IL-6, IL-1β, CXCL1, MCP-1, and TGF-β1). Conditioned media from senescent RTECs promoted activation and extracellular matrix gene expression in renal fibroblasts, establishing epithelial-mesenchymal crosstalk as a key driver of fibrogenic signaling. Although 1-AP activated aryl hydrocarbon receptor (AhR) but AhR inhibition failed to suppress SASP expression and fibroblast activation. On epigenetic level, 1-AP exposure on RTECs causes chromatin remodeling characterized by increased H3K9 acetylation and loss of H3K9me3 and H3K27me3, facilitating recruitment of the epigenetic reader BRD4 to SASP gene loci. Pharmacological inhibition of BRD4 suppressed SASP transcription, blocked paracrine activation of fibroblast and promotes apoptosis of RTECs. Hence, BRD4 may be a potential therapeutic target for treating pollution-related CKD.