Uremic Toxic Blood-Brain Barrier Disruption Mediated by AhR Activation Leads to Cognitive Impairment during Experimental Renal Dysfunction.
Adenine
Animals
Blood-Brain Barrier
/ diagnostic imaging
Carbon
/ pharmacology
Cognitive Dysfunction
/ etiology
Disease Models, Animal
Indican
/ blood
Male
Mice, Knockout
Nephrectomy
Neuropsychological Tests
Oxides
/ pharmacology
Permeability
Radiopharmaceuticals
/ metabolism
Rats
Rats, Sprague-Dawley
Receptors, Aryl Hydrocarbon
/ genetics
Renal Insufficiency, Chronic
/ complications
Single Photon Emission Computed Tomography Computed Tomography
Technetium Tc 99m Pentetate
/ metabolism
Uremia
/ blood
chronic kidney disease
dementia
uremia
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
23
07
2019
accepted:
30
03
2020
pubmed:
13
6
2020
medline:
25
2
2021
entrez:
13
6
2020
Statut:
ppublish
Résumé
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. 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 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 AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.
Sections du résumé
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
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
CONCLUSIONS
AhR activation by indoxyl sulfate, a uremic toxin, leads to blood-brain barrier disruption associated with cognitive impairment in animal models of CKD.
Identifiants
pubmed: 32527975
pii: ASN.2019070728
doi: 10.1681/ASN.2019070728
pmc: PMC7350986
doi:
Substances chimiques
Oxides
0
Radiopharmaceuticals
0
Receptors, Aryl Hydrocarbon
0
Carbon
7440-44-0
AST 120
90597-58-3
Adenine
JAC85A2161
Indican
N187WK1Y1J
Technetium Tc 99m Pentetate
VW78417PU1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1509-1521Informations de copyright
Copyright © 2020 by the American Society of Nephrology.
Références
Nat Rev Neurol. 2009 Oct;5(10):542-51
pubmed: 19724248
PLoS One. 2012;7(9):e46604
pubmed: 23029555
Lancet Neurol. 2014 Aug;13(8):823-33
pubmed: 25030514
J Gerontol A Biol Sci Med Sci. 2018 Mar 2;73(3):393-399
pubmed: 29244090
Am J Kidney Dis. 2018 Sep;72(3):349-359
pubmed: 29398180
J Cereb Blood Flow Metab. 2020 Feb;40(2):328-340
pubmed: 30540219
Neuron. 2015 Jan 21;85(2):296-302
pubmed: 25611508
Sci Rep. 2019 Feb 28;9(1):3097
pubmed: 30816118
Dement Neuropsychol. 2017 Jul-Sep;11(3):221-226
pubmed: 29213518
Dis Model Mech. 2015 Jul 1;8(7):733-42
pubmed: 26035380
Sci Rep. 2019 Dec 31;9(1):20388
pubmed: 31892730
Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6731-6
pubmed: 8692887
Transl Stroke Res. 2020 Feb;11(1):122-134
pubmed: 31055735
Semin Dial. 2011 May-Jun;24(3):327-37
pubmed: 21682773
J Pharmacol Exp Ther. 2008 Sep;326(3):829-37
pubmed: 18550693
Toxins (Basel). 2018 Jul 22;10(7):
pubmed: 30037144
J Clin Med. 2018 Oct 17;7(10):
pubmed: 30336612
Nephron Exp Nephrol. 2014;128(1-2):1-8
pubmed: 25376195
Circ J. 2013;77(1):224-30
pubmed: 23037589
J Am Soc Nephrol. 2013 Feb;24(3):353-63
pubmed: 23291474
J Am Soc Nephrol. 2008 Jul;19(7):1360-70
pubmed: 18385426
Clin J Am Soc Nephrol. 2018 Jan 6;13(1):109-117
pubmed: 29046290
PLoS One. 2014 Oct 17;9(10):e109113
pubmed: 25330005
Nat Med. 2019 Feb;25(2):270-276
pubmed: 30643288
Lancet. 2013 Jul 27;382(9889):339-52
pubmed: 23727170
J Thromb Haemost. 2007 Jun;5(6):1302-8
pubmed: 17403109
Life Sci. 2014 Sep 15;113(1-2):55-9
pubmed: 25107329
Clin J Am Soc Nephrol. 2019 Apr 5;14(4):567-575
pubmed: 30890576
J Neurochem. 2013 May;125(3):430-45
pubmed: 23240617
Am J Kidney Dis. 2011 Jan;57(1 Suppl 1):A8, e1-526
pubmed: 21184928
J Am Soc Nephrol. 2018 Mar;29(3):1063-1072
pubmed: 29343519
Vet J. 2018 Feb;232:70-77
pubmed: 29428096
J Am Geriatr Soc. 2010 Feb;58(2):338-45
pubmed: 20374407
Nephrology (Carlton). 2018 Jan;23(1):5-11
pubmed: 29030945
Physiol Rev. 2019 Jan 1;99(1):21-78
pubmed: 30280653
PLoS One. 2013 Jul 09;8(7):e66518
pubmed: 23874392
Pharmacol Biochem Behav. 1996 Feb;53(2):277-83
pubmed: 8808132
J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Aug 1;879(23):2281-6
pubmed: 21727042
Toxins (Basel). 2014 Jun 04;6(6):1742-60
pubmed: 24902077
Kidney Int. 2018 Apr;93(4):986-999
pubmed: 29395338
Toxins (Basel). 2018 Oct 07;10(10):
pubmed: 30301260
Int J Hypertens. 2011;2011:232683
pubmed: 21876786
J Am Soc Nephrol. 2019 Feb;30(2):336-345
pubmed: 30679381
Int J Cardiol. 2019 Jan 1;274:179-185
pubmed: 30177235
J Neurol Sci. 1992 Oct;112(1-2):96-105
pubmed: 1469446
Ren Fail. 2014 Mar;36(2):217-21
pubmed: 24168712
Nephrol Dial Transplant. 2014 Mar;29(3):529-38
pubmed: 24030834
Paediatr Anaesth. 2014 Jul;24(7):749-59
pubmed: 24725211
Contrib Nephrol. 2013;179:24-34
pubmed: 23652446
Sci Rep. 2016 Mar 02;6:22526
pubmed: 26932318
Front Pharmacol. 2017 Jun 12;8:370
pubmed: 28659803
Nephrol Ther. 2011 Feb;7(1):10-7
pubmed: 21050832
Cereb Cortex. 2015 Feb;25(2):472-81
pubmed: 24035904
Kidney Blood Press Res. 2011;34(6):430-8
pubmed: 21709424
Circulation. 2014 Dec 2;130(23):2040-51
pubmed: 25359166
J Am Soc Nephrol. 2015 Apr;26(4):876-87
pubmed: 25145928
J Biol Chem. 2009 Jan 30;284(5):2690-6
pubmed: 19054769
Behav Brain Res. 1988 Nov 1;31(1):47-59
pubmed: 3228475
J Biol Chem. 1997 Jul 25;272(30):18526-9
pubmed: 9228014
J Pharmacol Toxicol Methods. 2013 Sep-Oct;68(2):197-207
pubmed: 23732959
Int J Stroke. 2016 Jan;11(1):117-26
pubmed: 26763027
Front Behav Neurosci. 2014 Mar 13;8:78
pubmed: 24659961
J Exp Stroke Transl Med. 2009 Jan 1;2(2):2-27
pubmed: 20369026
Mol Pain. 2011 Jul 29;7:55
pubmed: 21801409
Crit Care. 2019 Feb 11;23(1):42
pubmed: 30744667
Life Sci. 2016 Sep 15;161:27-36
pubmed: 27493078
J Am Soc Nephrol. 1994 Jun;4(12):2023-31
pubmed: 7919155
J Am Soc Nephrol. 2004 Jul;15(7):1904-11
pubmed: 15213280
J Cereb Blood Flow Metab. 2000 Nov;20(11):1513-28
pubmed: 11083226
Kidney Int. 2013 Oct;84(4):733-44
pubmed: 23636172
Toxins (Basel). 2017 Dec 28;10(1):
pubmed: 29283413