Abstract
Mounting evidence suggests that the blueprint of chronic renal disease is established during early development by environmental cues that dictate alterations in differentiation programming. Here we show that aryl hydrocarbon receptor (AHR), a lig-and-activated basic helix-loop-helix-PAS homology domain transcription factor, disrupts murine renal differentiation by interfering with Wilms tumor suppressor gene (WT1) signaling in the developing kidney. Embryonic kidneys of C57BL/6J Ahr⁻/⁻ mice at gestation d (GD) 14 showed reduced condensation in the nephrogenic zone and decreased numbers of differentiated structures compared with wild-type mice. These deficits correlated with increased expression of the (+) 17aa Wt1 splice variant, decreased mRNA levels of Igf-1 rec., Wnt-4 and E-cadherin, and reduced levels of 52 kDa WT1 protein. AHR knockdown in wild-type embryonic kidney cells mimicked these alterations with notable increases in (+) 17aa Wt1 mRNA, reduced levels of 52 kDa WT1 protein, and increased (+) 17aa 40-kDa protein. AHR downregulation also reduced Igf-1 rec., Wnt-4, secreted frizzled receptor binding protein-1 (sfrbp-1) and E-cadherin mRNAs. In the case of Igf-1 rec. and Wnt-4, genetic disruption was fully reversed upon restoration of cellular Wt1 protein levels, confirming that functional interactions between AHR and Wt1 represent a likely molecular target for renal developmental interference.
Highlights
The fetal basis of adult renal disease in humans first was suggested by Barker and colleagues in studies showing that intrauterine growth restriction has a negative influence on the development of the cardiovascular system, and favors the occurrence of hypertension, insulin resistance, hypercholesterolemia and hyperuricemia later in life [1]
To examine the role of aryl hydrocarbon receptor (AHR) during nephrogenesis in vivo, renal cell differentiation was monitored in gestation d (GD):14 embryos of Ahr+/+ and Ahr–/– mice
The embryonic kidneys of Ahr–/– mice expressed higher levels of the (+) 17aa Wt1 splice variant (Figure 1C), a change that correlated with lower levels of Igf-1 rec., Wnt-4 and E-cadherin mRNAs and reduced levels of 52 kDa Wt1 protein (Figures 1D, E)
Summary
The fetal basis of adult renal disease in humans first was suggested by Barker and colleagues in studies showing that intrauterine growth restriction has a negative influence on the development of the cardiovascular system, and favors the occurrence of hypertension, insulin resistance, hypercholesterolemia and hyperuricemia later in life [1]. These findings have been confirmed in experimental animal models of human disease [2,3], indicating that highly conserved signaling pathways exist that control differentiation programming through interaction with environmental cues that define complex genetic interactions at the cellular level. The developmental functions of Ahr may be mediated by physiological ligands generated by aspartate aminotransferase, an en-
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