Molecular interactions between the Wilms' tumor transcription factor and the aryl hydrocarbon receptor during nephrogenesis and its impact on fetal programming of renal disease

Abstract

Embryonic development requires the orchestration of temporally precise genetic events that culminate in the formation of a complete organism. The molecular mechanisms responsible for ontogenesis are regulated by environmental and somatic factors in utero that activate or repress the expression of numerous genetic elements resulting in fetal programming of adult diseases. The aryl hydrocarbon receptor (AHR) is an important nuclear transcription factor both during embryogenesis and throughout maturity in multiple organisms. Building upon interesting studies establishing a direct, novel link between AHR and post-transcriptional regulation of the Wilms' tumor suppressor (WT1 ) gene, the overall goal of the project was to elucidate the role of AHR in the regulation of WT1 during nephrogenesis. The evidence shows that in utero exposure to environmentally relevant exposures of benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon (PAH) and AHR ligand, results in AHR allele-specific deficits in renal development manifested as decreased numbers of glomeruli, induction in urinary albumin, and podocytopenia. These findings were consistent with metanephric and organ culture data where PAHs caused AHR allele-specific reduction in renal cell differentiation markers, dysregulation of WT1 mRNA splice variants, and decreases in direct WT1 transcriptional targets. Observed deficits were linked to disruption of constitutive AHR signaling, as siRNA-mediated AHR degradation reproduced similar effects. Collectively, this evidence defined a novel role for the AHR in renal development and in fetal programming of PAH-induced environmental disease.