Abstract
Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.
Highlights
Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB)
Decreased expression of tight-junction proteins were observed in non-chronic kidney disease (CKD) adipose microcirculation exposed to the uraemic toxin trimethylamine N-oxide (TMAO), further suggesting that TMAO could act as an important mediator in the disruption of the gut-blood barrier (GBB), and by similarity the BBB
We find that in fat microvessels from non CKD controls incubated with TMAO resulted in reduced expression of tight-junction proteins claudin-5, occludin and junction adhesion molecule-1 (JAM-1)
Summary
Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it reduces expression of tight-junction proteins that confer BBB maintenance. The impairment in BBB function may further lead to increased vascular permeability allowing entry of toxic substances into the CNS, resulting in damage that may manifest as depression and cognitive impairments that are observed in the cognitive dysfunction in patients with Alzheimer’s d isease[14]. A number of candidate biomarkers for increased BBB permeability have been introduced, such as: brain-derived neurotrophic factor (BDNF) and neuron-specific enolase (NSE). NSE has been introduced as a promising biomarker of future brain-related vascular events and subclinical brain damage among asymptomatic hypertensive patients[20]
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