The Role of Aryl Hydrocarbon Receptor-Dependent Signaling Pathway in the Profibrotic Effects of Dioxin-like Compounds in Human Renal Tubular Epithelial Cells.

The aryl hydrocarbon receptor (AhR) signaling pathway mediates nephrotoxic compound effects on the kidney, although its mechanisms are incompletely understood. Given that renal tubulointerstitial fibrosis is a central pathological feature of progressive kidney diseases, we investigated AhR-induced profibrotic events at the molecular and cellular levels in human renal tubular epithelial cells (HKC). We found that the AhR activation by the potent agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promoted epithelial-mesenchymal transition (EMT) and inflammatory responses. This was evidenced by a 56.19% decrease in E-cadherin; 1.87-, 2.39-, and 8.27-fold increases in fibronectin, MMP9, and IL-6, respectively; and a 37.77% enhancement in cell migration. Transcriptome analysis and experimental validations confirmed the consistent dysregulation of these markers. Moreover, we found the profibrotic effects of the known nephrotoxic phytochemical aristolactam I (AL-I) also involving activation of AhR and consistent regulation of the above marker genes, primarily via the AhR. In addition, the transcriptome data further suggested that AhR activation may indirectly induce the profibrotic epidermal growth factor receptor (EGFR) pathway by upregulating AREG, EREG, and TGF-α, indicating crosstalk between AhR and EGFR. Given the wide variety of AhR-active chemicals, these AhR-EMT/inflammation-related markers could be used to screen nephrotoxicity of emerging dioxin-like pollutants and toxic phytochemicals.