ARYL hydrocarbon receptor agonist ficz alleviated rhabdomyolysis-induced AKI by regulating inflammation and apoptosis

Background: Aryl hydrocarbon receptors (AhR) are ubiquitous in the cytoplasm of various cells in various organs. They can bind to multiple ligands and affect different downstream pathways. Previous studies have found that activating AhR could alleviate inflammation and apoptosis through the NFκB pathway in ulcerative colitis, psoriasis and metabolic diseases induced by high-fat diet. However, whether AhR agonist FICZ can alleviate acute kidney injury (AKI) remains unclear. Thus, we explored the role of FICZ in AKI and its related mechanisms through rhabdomyolysis-induced AKI model. Methods: C57BL/6 mice were randomly divided into three groups: control, glycerol and glycerol+FICZ. The glycerol group were injected group were injected with glycerol at bilateral back limbs. The glycerol+FICZ group was administered intraperitoneally for 3 days before the glycerol injection. The mice were sacrificed at 24h after the glycerol injection, blood and organs were collected. Renal histological injury was measured by PAS staining. Renal tissues of mice were analyzed by immunohistochemical, immunofluorescence, western blot and qPCR assay. Results: Immunofluorescence staining and western blot showed that AhR was mainly expressed in proximal renal tubular epithelial cells, and the expression of AhR was decreased in rhabdomyolysis-induced AKI. Activation of AhR by FICZ pretreatment significantly reduced serum creatinine (Scr), urea and creatine kinase (CK) levels, as well as attenuated renal tubular damage in glycerol-injured kidneys. AhR activation also resulted in reduced TUNEL-positive tubular cells, suppressed cleaved caspase-3, BAX levels, and preserved Bcl-2, Bcl-XL expression, indicating that FICZ regulated tubular cell apoptosis. Moreover, the expressions of p-P65, p-iκBα and inflammatory factors IL-6, IL-1β and TNFα in the glycerol+FICZ group were significantly reduced, comparing with the glycerol group. The transcription levels of those inflammatory factors, MCP1 and IFNγ genes were detected by qPCR. These data suggested that FICZ showed renoprotective effects also by regulating inflammation via the NFκB pathway. Conclusions: In summary, our findings demonstrated that AhR agonist FICZ protects against rhabdomyolysis-induced AKI via the regulation of inflammation and apoptosis in tubular epithelial cells.