Subchronic co-exposure to dibutyl phthalate and benzo(a)pyrene exacerbates renal inflammation and fibrosis in rat: Crosstalk between tubular epithelial cells and fibroblasts

Abstract

Dibutyl phthalate (DBP) and benzo(a)pyrene (BaP) are commonly organic pollutants that have been simultaneously detected in environmental media, posing a significant risk to human health. However, the precise impacts and underlying mechanisms of subchronic co-exposure to DBP and BaP on the kidney remain incompletely comprehended. In this research, we evaluated the combined impact of DBP and BaP on the kidney in vivo and in vitro models. The findings exhibited that subchronic co-exposure to environmental concentrations of DBP and BaP engendered more severe inflammation and renal fibrosis than single exposure. Mechanistically, DBP and BaP co-exposure may activate the renin-angiotensin system (RAS) signaling through fibroblast growth factor 23 (FGF-23), potentially damaging renal tubular epithelial cells (RTECs). The injured RTECs further produced significant amounts of pro-inflammatory and pro-fibrotic factors, which activate surrounding fibroblasts, leading to excessive extracellular matrix (ECM) deposition and ultimately renal fibrosis. Notably, knockdown FGF-23 alleviated activation of the RAS signaling, as well as ECM production and deposition induced by DBP and BaP subchronic co-exposure. Collectively, our results indicated that DBP and BaP co-exposure may activate fibroblasts via FGF-23 activation of RAS signaling in RTECs, thereby accelerating the development of renal fibrosis.