Mickaël Bobot1,2,3, Laurent Thomas2,3, Anaïs Moyon2,3,4, Samantha Fernandez2, Nathalie McKay3, Laure Balasse2, Philippe Garrigue2,3,4, Pauline Brige2,5, Sophie Chopinet2,5,6, Stéphane Poitevin3, Claire Cérini3, Philippe Brunet7,3, Françoise Dignat-George3, Stéphane Burtey7,3, Benjamin Guillet2,3,4, Guillaume Hache8,3,9. 1. Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, Assistnce Publique - Hôpitaux de Marseille, Marseille, France mickael.bobot@ap-hm.fr guillaume.hache@univ-amu.fr. 2. Centre Européen de recherche en Imagerie Médicale, Aix Marseille Université, Centre National de la Recherche Scientifique, Marseille, France. 3. Centre de Recherche en Cardiovasculaireet Nutrition, Aix Marseille Université, Institut National de la Santé et de la Recherche Médicale, Institut National de Recherche pour l'agriculture, l'alimentation et l'environnement, Marseille, France. 4. Service de Radiopharmacie, Assistnce Publique - Hôpitaux de Marseille, Marseille, France. 5. Laboratoire d'Imagerie Interventionelle Expérimentale, Aix-Marseille Université, Marseille, France. 6. Service de Chirurgie générale et transplantation hépatique, Hôpital de la Timone, Assistnce Publique - Hôpitaux de Marseille, Marseille, France. 7. Centre de Néphrologie et Transplantation Rénale, Hôpital de la Conception, Assistnce Publique - Hôpitaux de Marseille, Marseille, France. 8. Centre Européen de recherche en Imagerie Médicale, Aix Marseille Université, Centre National de la Recherche Scientifique, Marseille, France mickael.bobot@ap-hm.fr guillaume.hache@univ-amu.fr. 9. Pharmacie, Hôpital de la Timone, Assistnce Publique - Hôpitaux de Marseille, Marseille, France.
Abstract
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 99mTc-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 99mTc-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.
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 99mTc-DTPA, an imaging marker of blood-brain barrier permeability. RESULTS: In CKDrats, 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 99mTc-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-CKDAhR-/- 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.
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