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FO029COGNITIVE IMPAIRMENT WAS ASSOCIATED WITH BRAIN-BLOOD BARRIER PERMEABILITY IN TWO MODELS OF CHRONIC KIDNEY DISEASE IN RATS
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- 자료유형학술지논문
- 저자명Bobot, Mickaël,Hache, Guillaume,Fernandez, Samatha,Balasse, Laure,Brige, Pauline,Chopinet, Sophie,Thomas, Laurent,Mckay, Nathalie,Burtey, Stéphane,Guillet, Benjamin
- 학회/출판사/기관명Oxford University Press
- 출판년도2019
- 언어영어
- 학술지명/학위논문주기Nephrology, dialysis, transplantation
- 발행사항Vol.34No.1[2019]_x000D_
- ISBN/ISSN
- 소개/요약INTRODUCTION: Chronic kidney disease (CKD) patients have a higher risk of developing cognitive impairment. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including direct toxicity of uremic toxins or cerebral endothelial dysfunction could be involved. Thus the aim of our preclinical work was to characterize cerebral and neurobehavioral abnormalities in two models of CKD in rats. METHODS: We induced CKD in male Sprague Dawley rats by Adenine rich diet (ARD) (0.5%) during 4 weeks or 5/6 nephrectomy. CKD was assessed by biochemistry, uremic toxins dosage in serum, and histology. Behavioral assessment explored overall neurological function by the mNSS, locomotion and sensorimotor function by the foot fault test and the adhesive removal test, respectively, and the short term memory by the novel object recognition (NOR) test. Brain-Blood Barrier (BBB) permeability was evaluated by 99mTc-DTPA SPECT/CT imaging. To evaluate the involvement of uremic toxins, we added a group of ARD-induced CKD rats with IS in drinking water (1g/L) (ARD+IS). RESULTS: Compared to control, we described in ARD rats i) an increase in creatininemia and BUN associated with an increase in indoxyl sulfate (IS) in serum and an increased in fibrosis and tubuloinstestitial damage in kidneys, ii) a decrease in the discrimination index in NOR test (0.2±0.3 vs 0.7±0.3; p<0.01; n=7), iii) an increase in 99mTc-DTPA uptake in brain (0.086±0.025%AI/g vs 0.003±0.010%AI/g; p<0.001; n=7). Interestingly, we highlighted a significant correlation between 99mTc-DTPA uptake in brain and both the discrimination index in NOR (r=-0.86, p<0.01) and IS concentrations in serum (r=0.68, p<0.01). Similar results were observed in 5/6 nephrectomy rats (n=8). Compared to ARD rats, we observed in ARD+IS rats i) an increase in IS concentrations in serum (424±95umol/L vs 65±28umol/L; p<0.001; n=6), ii) a decrease in the discrimination index in NOR test (-0.6±0.2 vs 0.2±0.3; p=0.001; n=6) and iii) an increase in 99mTc-DTPA uptake in brain (0.104±0.018%AI/g vs 0.080±0.026%AI/g; p=0.08; n=6. CONCLUSIONS: We report for the first time an increase in BBB permeability in two models of CKD in rats, which was associated with cognitive impairment and increased IS in serum. Interestingly, adding IS on drinking water worsened both impairments, suggesting a direct toxicity of IS. Further studies are needed to decipher the mechanisms involved.
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