A new study reports activation of the aryl hydrocarbon receptor (AHR) in various tissues in models of chronic kidney disease (CKD) and acute kidney injury (AKI). “AHR signalling is emerging as a mediator of uraemic toxicity, especially of indolic solutes, which are AHR ligands,” says lead researcher Vipul Chitalia. “In this study we investigated the systemic activation of AHR, which may provide clues to the effects of uraemia on different organs.”

To investigate AHR activation, the researchers used transgenic mice with a β-galactosidase reporter gene downstream of the DNA-binding domain for activated AHR. They report upregulation of β-galactosidase — indicating AHR activation — in the renal tubules, cardiac myocytes, hepatocytes and cerebral cortex microvasculature in mice with adenine-induced CKD and in mice with high plasma levels of indoxyl sulfate similar to those seen in end-stage renal disease. In both models, the levels of indoxyl sulfate correlated with β-galactosidase expression in the various tissues. “AHR activation in the central nervous system (CNS) suggests a role of uraemic solutes in neurocognitive deficiencies in CKD,” comments Joshua Walker, first author of the study.

In mice with ischaemia–reperfusion injury, the plasma levels of indoxyl sulfate were increased at 24 h after surgery but then rapidly decreased, whereas the mRNA expression of β-galactosidase in the kidneys and liver, but not in the heart and CNS, was increased at 24 h and 48 h after surgery. The researchers suggest that this persistent AHR signalling following AKI might negatively affect the survival of the renal tubules.

“The results of our study are hypothesis-generating; we believe they will seed future investigations into uraemic toxicity,” says Chitalia. “First, knowing where AHR is active in various tissues and organs in response to uraemic solutes allows us to begin to examine which genes AHR regulates under these conditions. Second, from a clinical standpoint, our findings provide evidence to support the use of AHR inhibitors as therapeutics to combat complications that are associated with CKD and uraemia.”