Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction

Significance Statement Uremic toxicity may play a role in the elevated risk of developing cognitive impairment observed in patients with CKD. Some uremic toxins, such as indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR). The authors found that cognitive impairment in three models of CKD in rats is correlated with serum levels of indoxyl sulfate as well as blood-brain barrier disruption as detected by SPECT/CT imaging. Using AhR −/− knockout mice, the authors described for the first time that indoxyl sulfate–induced activation of AhR is responsible for blood-brain barrier disruption. These findings demonstrate that blood-brain barrier disruption seems to be an important mechanism involved in cognitive impairment in the context of CKD and that AhR may be a promising therapeutic target to prevent cognitive impairment in CKD. Background Uremic toxicity may play a role in the elevated risk of developing cognitive impairment found among patients with CKD. Some uremic toxins, like indoxyl sulfate, are agonists of the transcription factor aryl hydrocarbon receptor (AhR), which is widely expressed in the central nervous system and which we previously identified as the receptor of indoxyl sulfate in endothelial cells. Methods To characterize involvement of uremic toxins in cerebral and neurobehavioral abnormalities in three rat models of CKD, we induced CKD in rats by an adenine-rich diet or by 5/6 nephrectomy; we also used AhR −/− knockout mice overloaded with indoxyl sulfate in drinking water. We assessed neurologic deficits by neurobehavioral tests and blood-brain barrier disruption by SPECT/CT imaging after injection of 99m Tc-DTPA, an imaging marker of blood-brain barrier permeability. Results In CKD rats, we found cognitive impairment in the novel object recognition test, the object location task, and social memory tests and an increase of blood-brain barrier permeability associated with renal dysfunction. We found a significant correlation between 99m Tc-DTPA content in brain and both the discrimination index in the novel object recognition test and indoxyl sulfate concentrations in serum. When we added indoxyl sulfate to the drinking water of rats fed an adenine-rich diet, we found an increase in indoxyl sulfate concentrations in serum associated with a stronger impairment in cognition and a higher permeability of the blood-brain barrier. In addition, non-CKD AhR −/− knockout mice were protected against indoxyl sulfate–induced blood-brain barrier disruption and cognitive impairment. Conclusions AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.