Aryl Hydrocarbon Receptor Promotes Kidney Fibrosis via Accelerating Cell Senescence in Tubular Epithelial Cells

Background: Chronic kidney disease (CKD) has a high prevalence worldwide and tubulointerstitial fibrosis is considered the final convergent pathway of progressive CKD regardless of etiology. However, mechanisms underlying kidney injury-induced fibrosis largely remain unknown. The aryl hydrocarbon receptor (AhR) is a well-known ligand-activated cytoplasmic transcription factor that contributes to cellular responses against environmental toxins and carcinogens. AhR activity is strongly implicated throughout the course of CKD but its certain role and underlying mechanism remains unknown. Methods: AhR expression was examined in the kidney specimens of CKD patients as well as in the kidneys of mouse models with experimental kidney fibrosis (unilateral ureteral obstruction [UUO], adenine nephropathy [Aden], and aristolochic acid-induced nephrotoxicity [AA]). The potential role of AhR in renal fibrosis was further validated by AhR conditional knock out in mice or AhR siRNA in TCMK-1 cells. ATAC-seq combined with RNA-seq was employed to explore the underlying mechanisms. Results: Increased AhR expression was observed in the kidneys of both CKD patients of various etiology and three mouse models with kidney fibrosis. The elevated AhR expression was mainly located within tubualr cells and was associated with the levels of Scr and eGFR in CKD patients. Tubule-specific knock out of AhR in mice alleviated UUO- and Aden-induced renal fibrosis. Mechanistically, in tubular epithelial cells, AhR exerted a profibrotic role via a NF-κB-dependent signaling. AhR promoted the activation of NF-κB by regulating the transcription of IκBα and thus accelerating tubular senescence. Pharmacological inhibition of AhR ameliorated tubular senescence and renal fibrosis in both animal models and TCMK-1 cells. Conclusion: Tubular AhR plays an important role in kidney fibrosis by suppressing profibrotic NF-κB signaling. Hence, our findings suggest that modulating the activity of tubular AhR may be a new therapeutic option for treating tubulointerstitial fibrosis and subsequent CKD. Funding: Government Support – Non-U.S.