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. 2022 Mar 15;12(1):4414.
doi: 10.1038/s41598-022-08387-7.

Blood-brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins

Leah Hernandez #  1 , Liam J Ward #  1 , Samsul Arefin  1 , Thomas Ebert  1 , Agne Laucyte-Cibulskiene  1   2 ; GOING-FWD Collaborators; Olof Heimbürger  1 , Peter Barany  1 , Lars Wennberg  3 , Peter Stenvinkel  1 , Karolina Kublickiene  4
Collaborators, Affiliations

Blood-brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins

Leah Hernandez et al. Sci Rep. .

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.

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Conflict of interest statement

PS serves on Scientific Advisory Boards of Baxter, AstraZeneca and REATA. All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Analysis of serum biomarkers in haemodialysis (HD) and non-CKD controls (control). (A) Brain-derived neurotrophic factor (BDNF), (B) Neuron-specific enolase (NSE) were measured by enzyme-linked immunosorbent assay (ELISA). (C) Trimethylamine N-oxide (TMAO) was measured by liquid chromatography-mass spectrometry (LC–MS). The number of samples (n) that each analyte was detected in is noted for each group. Data presented at median and interquartile range. Statistical significance, ***p < 0.001, ****p < 0.0001. (D) Spearman’s correlation between BDNF and TMAO levels. (E) Spearman’s correlation between NSE and TMAO levels.
Figure 2
Figure 2
Analysis of soluble CD14 (sCD14) levels in haemodialysis (HD) and non-CKD controls (control). (A) Soluble CD14 levels. The number of samples (n) that each analyte was detected in is noted for each group. Data presented at median and interquartile range. Statistical significance, ***p < 0.001, ****p < 0.0001. (B) Spearman’s correlation between sCD14 and trimethylamine N-oxide (TMAO) levels.
Figure 3
Figure 3
Sex-related differences in haemodialysis patients with self-assessed depression and serum concentrations of biomarkers; (A) brain-derived neurotrophic factor (BDNF), (B) neuron-specific enolase (NSE), (C) trimethylamine N-oxide (TMAO). The number of samples (n) that each analyte was detected in is noted for each group. Data presented at median and interquartile range when appropriate. Statistical significance, *p < 0.05.
Figure 4
Figure 4
Mortality and serum concentration of biomarker in haemodialysis patients; (A) brain-derived neurotrophic factor (BDNF), (B) neuron-specific enolase (NSE), and (C) trimethylamine N-oxide (TMAO). The number of samples (n) that each analyte was detected in is noted for each group. Data presented at median and interquartile range when appropriate. Statistical significance, *p < 0.05, **p < 0.01.
Figure 5
Figure 5
Tight junction protein expression in subcutaneous adipose tissue. (A) Immunofluorescence staining of tight junction proteins (red) claudin-5, occludin, and JAM-1, nuclear staining with DAPI (blue), endothelial marker CD31 (green) in subcutaneous tissue of kidney transplant recipients and donors. Bar = 100 µm. Expression of tight junction proteins (B) claudin-5, (C) occludin and (D) JAM-1 in subcutaneous tissue of kidney transplant recipients and donors. Results expressed in medians and interquartile range. Statistical significance *p < 0.05, **p < 0.01.
Figure 6
Figure 6
TMAO incubation and tight junction protein expression in subcutaneous adipose tissue. (A) Immunofluorescence staining of tight junction proteins (red) claudin-5, occludin, and JAM-1, nuclear staining with DAPI (blue), endothelial marker CD31 (green) in subcutaneous tissue incubated with (A) TMAO and (B) control media. Bar = 100 µm. Expression of tight junction proteins (B) claudin-5, (C) occludin and (D) JAM-1 in subcutaneous tissue after incubation with TMAO and control media. Results expressed in medians and interquartile range. Statistical significance *p < 0.05, **p < 0.01.
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