Research Paper Volume 15, Issue 20 pp 10972—10995
Chronic kidney disease causes blood-brain barrier breakdown via urea-activated matrix metalloproteinase-2 and insolubility of tau protein
- 1 Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo City, Tokyo 113-8519, Japan
- 2 Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo City, Tokyo 113-8519, Japan
- 3 Center for Brain Integration Research, Tokyo Medical and Dental University, Bunkyo City, Tokyo 113-8519, Japan
Received: May 30, 2023 Accepted: October 2, 2023 Published: October 25, 2023
https://doi.org/10.18632/aging.205164How to Cite
Copyright: © 2023 Matsuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Chronic kidney disease (CKD) causes cognitive impairment and contributes to the overall global burden of dementia. However, mechanisms through which the kidneys and brain communicate are not fully understood. We established a CKD mouse model through adenine-induced tubulointerstitial fibrosis. Novel object recognition tests indicated that CKD decreased recognition memory. Sarkosyl-insoluble-proteomic analyses of the CKD mouse hippocampus revealed an accumulation of insoluble MAPT (microtubule-associated protein tau) and RNA-binding proteins such as small nuclear ribonucleoprotein U1 subunit 70 (SNRNP70). Additionally, there was an accumulation of Immunoglobulin G (IgG), indicating blood-brain barrier (BBB) breakdown. We identified that expressions of essential tight-junction protein claudin-5 and adherens-junction protein platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) were decreased in the brain endothelial cells of CKD mice. We determined urea as a major uremic solute that dose dependently decreased both claudin-5 and PECAM-1 expression in the mouse brain endothelial cell line bEnd.3 cells. Gelatin zymography indicated that the serum of CKD mice activated matrix metalloproteinase-2 (MMP2), while marimastat ameliorated the reduction of claudin-5 expression by urea in bEnd.3 cells. This study established a brain proteomic signature of CKD indicating BBB breakdown and insolubility of tau protein, which are pathologically linked to Alzheimer's disease. Urea-mediated activation of MMP2 was partly responsible for BBB breakdown in CKD.
Abbreviations
AD: Alzheimer’s disease; α-SMA: α-smooth muscle actin; BBB: blood-brain barrier; BSA: bovine serum albumin; CKD: Chronic kidney disease; CNS: central nervous system; DEGs: differentially expressed genes; DIA: Data-independent acquisition; DMSO: dimethyl sulfoxide; eGFR: estimated glomerular filtration rate; GO: gene ontology; IgG: immunoglobulin G; IS: indoxyl sulfate; KDIGO: Kidney Disease Improving Global Outcomes; MAPT: microtubule-associated protein tau; MMP: matrix metalloproteinase; MCI: mild cognitive impairment; NOR: novel object recognition; OR: odds ratio; PFA: paraformaldehyde; PECAM-1: platelet endothelial cell adhesion molecule-1; PBS: phosphate buffered saline; snRNP70: small nuclear ribonucleoprotein U1 subunit 70; TJPs: tight-junction proteins; TMAO: trimethylamine N-oxide; WBC: white blood cell.