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Neurological sequel of chronic kidney disease: From diminished Acetylcholinesterase activity to mitochondrial dysfunctions, oxidative stress and inflammation in mice brain.

ABSTRACT: With increasing prevalence, chronic kidney disease (CKD) has become a global health problem. Due to the retention of uremic toxins, electrolytes and water, and the resultant metabolic disturbances, CKD affects several organs, including the nervous system. Thus, CKD patients suffer from several neurological complications, including dementia, cognitive impairment, motor abnormalities, depression, and mood and sleep disturbances. However, the mechanisms underlying the neurological complications are least elucidated. We have recently reported a highly reproducible mice model of CKD induced by high adenine diet, which exhibited psychomotor behavioral abnormalities and blood-brain barrier disruption. In the present study, using the mice model, we have investigated psycho-motor and cognitive behaviour, and the neurochemical and histopathological alterations in brain relevant to the observed behavioural abnormalities. The results demonstrate global loss of Acetylcholinesterase activity, and decrease in neuronal arborisation and dendritic spine density in discrete brain regions, of the CKD mice. Oxidative stress, inflammation, and mitochondrial dysfunctions were found in specific brain regions of the mice, which have been regarded as the underlying causes of the observed neurochemical and histopathological alterations. Thus, the present study is of immense importance, and has therapeutic implications in the management of CKD-associated neurological complications.

SUBMITTER: Mazumder MK

PROVIDER: S-EPMC6395638 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Neurological sequel of chronic kidney disease: From diminished Acetylcholinesterase activity to mitochondrial dysfunctions, oxidative stress and inflammation in mice brain.

Mazumder Muhammed Khairujjaman MK Paul Rajib R Bhattacharya Pallab P Borah Anupom A

Scientific reports 20190228 1

With increasing prevalence, chronic kidney disease (CKD) has become a global health problem. Due to the retention of uremic toxins, electrolytes and water, and the resultant metabolic disturbances, CKD affects several organs, including the nervous system. Thus, CKD patients suffer from several neurological complications, including dementia, cognitive impairment, motor abnormalities, depression, and mood and sleep disturbances. However, the mechanisms underlying the neurological complications are ...[more]

PMID: 30816118

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Project description:Background: Increased arterial stiffness and vascular endothelial dysfunction are important nontraditional cardiovascular risk factors evident in patients with CKD. Vascular oxidative stress and inflammation may contribute to vascular dysfunction in CKD, but direct evidence is lacking.Methods: We assessed carotid-femoral pulse-wave velocity (arterial stiffness) and brachial artery flow-mediated dilation (vascular endothelial function) in participants with moderate-to-severe CKD (eGFR 15-59 ml/min per 1.73 m2) and in healthy controls. Change in brachial artery flow-mediated dilation after an acute infusion of ascorbic acid to inhibit vascular oxidative stress (versus saline) was also measured. Protein expression of vascular endothelial cells collected from a peripheral vein and ELISAs to assess circulating markers were also performed.Results: A total of 64 participants with CKD (mean±SD, 65±8 years) and 17 healthy controls (60±5 years) were included. Carotid-femoral pulse-wave velocity was greater in participants with CKD compared with healthy controls (1071±336 versus 732±128 cm/s; P<0.001). Brachial artery flow-mediated dilation was lower in participants with CKD compared with healthy controls (3.5%±2.8% versus 5.5%±3.2%; P=0.02). Circulating inflammation markers (C-reactive protein and IL-6) were elevated in the CKD group (P?0.02). Endothelial cell protein expression of NADPH (intensity versus human umbilical vein endothelial cell control, 1.48±0.28 versus 1.25±0.31; P=0.05) was greater in participants with CKD. However, ascorbic acid significantly improved brachial artery flow-mediated dilation in control participants (saline, 5.5±3.2; ascorbic acid, 6.8±3.6); as compared with participants with CKD (saline, 3.5±2.8; ascorbic acid, 3.6±3.2) (group×condition interaction P=0.04), suggesting vascular oxidative stress could not be overcome with ascorbic acid in participants with CKD.Conclusions: Vascular oxidative stress is present in CKD, which cannot be overcome with acute infusion of ascorbic acid.

Project description:Chronic ethanol ingestion mildly damages liver through oxidative stress and lipid oxidation, which is ameliorated by dietary supplementation with the anti-inflammatory β-amino acid taurine. Kidney, like liver, expresses cytochrome P450 2E1 that catabolizes ethanol with free radical formation, and so also may be damaged by ethanol catabolism. Sudden loss of kidney function, and not liver disease itself, foreshadows mortality in patients with alcoholic hepatitis [J. Altamirano, Clin. Gastroenterol. Hepatol. 2012, 10:65]. We found that ethanol ingestion in the Lieber-deCarli rat model increased kidney lipid oxidation, 4-hydroxynonenal protein adduction, and oxidatively truncated phospholipids that attract and activate leukocytes. Chronic ethanol ingestion increased myeloperoxidase-expressing cells in kidney and induced an inflammatory cell infiltrate. Apoptotic terminal deoxynucleotidyl transferase nick-end labeling-positive cells and active caspase-3 increased in kidney after ethanol ingestion, with reduced filtration with increased circulating blood urea nitrogen (BUN) and creatinine. These events were accompanied by release of albumin, myeloperoxidase, and the acute kidney injury biomarkers kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, and cystatin c into urine. Taurine sequesters HOCl from myeloperoxidase of activated leukocytes, and taurine supplementation reduced renal lipid oxidation, reduced leukocyte infiltration, and reduced the increase in myeloperoxidase-positive cells during ethanol feeding. Taurine supplementation also normalized circulating BUN and creatinine levels and suppressed enhanced myeloperoxidase, albumin, KIM-1, and cystatin c in urine. Thus, chronic ethanol ingestion oxidatively damages kidney lipids and proteins, damages renal function, and induces acute kidney injury through an inflammatory cell infiltrate. The anti-inflammatory nutraceutical taurine effectively interrupts this ethanol-induced inflammatory cycle in kidney.

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Neurological sequel of chronic kidney disease: From diminished Acetylcholinesterase activity to mitochondrial dysfunctions, oxidative stress and inflammation in mice brain.

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Neurological sequel of chronic kidney disease: From diminished Acetylcholinesterase activity to mitochondrial dysfunctions, oxidative stress and inflammation in mice brain.

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