Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction
| العنوان: | Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction |
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| المؤلفون: | Philippe Brunet, Pauline Brige, Nathalie McKay, Mickaël Bobot, Philippe Garrigue, Laure Balasse, Françoise Dignat-George, Sophie Chopinet, Samantha Fernandez, Claire Cerini, Stéphane Poitevin, Stéphane Burtey, Guillaume Hache, Laurent Thomas, Benjamin Guillet, Anaïs Moyon |
| المساهمون: | Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre Européen de Recherche en Imagerie médicale (CERIMED), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-École Centrale de Marseille (ECM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Imagerie Interventionnelle Expérimentale (LIIE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lucas, Nelly |
| المصدر: | Journal of the American Society of Nephrology Journal of the American Society of Nephrology, American Society of Nephrology, 2020, 31 (7), pp.1509-1521. ⟨10.1681/ASN.2019070728⟩ Journal of the American Society of Nephrology, 2020, 31 (7), pp.1509-1521. ⟨10.1681/ASN.2019070728⟩ J Am Soc Nephrol |
| بيانات النشر: | HAL CCSD, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Neuropsychological Tests, Nephrectomy, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Rats, Sprague-Dawley, chemistry.chemical_compound, 0302 clinical medicine, uremia, Indoxyl, Receptor, Mice, Knockout, biology, Oxides, General Medicine, 3. Good health, medicine.anatomical_structure, Blood-Brain Barrier, Nephrology, Knockout mouse, Technetium Tc 99m Pentetate, medicine.medical_specialty, Single Photon Emission Computed Tomography Computed Tomography, Central nervous system, Permeability, 03 medical and health sciences, Internal medicine, medicine, Animals, Dementia, Cognitive Dysfunction, Renal Insufficiency, Chronic, Transcription factor, business.industry, Adenine, Aryl hydrocarbon receptor, medicine.disease, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Carbon, Uremia, Rats, Disease Models, Animal, Basic Research, 030104 developmental biology, Endocrinology, Receptors, Aryl Hydrocarbon, chemistry, biology.protein, Radiopharmaceuticals, business, Indican, 030217 neurology & neurosurgery, chronic kidney disease, dementia |
| الوصف: | International audience; 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 Tc-99m-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 Tc-99m-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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1046-6673 1533-3450 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::73118d4add22256c3d54d2e12b649442 https://hal.inrae.fr/hal-03158259 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....73118d4add22256c3d54d2e12b649442 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10466673 15333450 |
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