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Abstract: FR-PO128

Cerebral Microvasculature Impairments Induced Dementia in CKD

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Xu, Jen, Harvard College, Cambridge, Massachusetts, United States
  • Lin, Hugo You-Hsien, University of California, Irvine, Irvine, California, United States
  • Ho, Li-lun, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
  • Lim, Kenneth, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Hiemstra, Thomas F., University of Cambridge, Cambridge, United Kingdom
  • Bonventre, Joseph V., Brigham and Women's Hospital , Boston, Massachusetts, United States
  • Lu, Tzongshi, Brigham and Women's Hospital , Boston, Massachusetts, United States
Background

Structural and functional impairments of brain microvasculature result in white matter hypo-perfusion and ischemia are major causes of Cerebral small vessel disease (CSVD). Recently, chronic kidney disease (CKD) has been identified as a significant risk factor for stroke and dementia as well as CSVD. Interestingly, both kidney and cerebral microvasculature share similar anatomical and physiologic characteristics particular in their endothelium. The goal of this study was to elucidate the molecular mechanisms of CKD induced cerebral microvasculature dysfunction and consequences neurological diseases.

Methods

CKD mice model was generated by 5/6 nephrectomy on C57BL/6 mice. Transcriptomic profiling of calcification medium (CM) and hyperglycemia medium (GM) treated primary human brain microvascular endothelial cells (HBMECs), in vitro, and human arteries collected from CKD (n=20), CAD (n=15) and healthy donors (n=20) were subjected to RNA sequencing, ex vivo. In addition, incidence and risk of dementia in CKD from a population-based study using the Taiwan National Health Insurance database with 1,000,000 subjects from 2000 to 2009.

Results

Our results showed that CKD mice had decreased myelinated nerve fibers in the corpus callosum and cerebral cortex and loosening myelinated fibers in the corpus callosum. Collagen IV accumulation in brain microvasculature and serum phosphate levels were significant increased in CKD mice compared to control mice. Tight junction (TJ) proteins occludin, claudin-5, and ZO-1 were down-regulated in both CM/GM-treated primary HBMECs. In human arteries, both claudin-5 and ZO-1 genes were down-regulated in CKD group together with anti-apoptotic gene Bcl2. Furthermore, cell viability decreased and caspase-3 mediated apoptosis increased as well as Collagen IV expression in CM treated HBMECs. The subsequent risks of dementia were 2.208-fold (Diabetes + CKD); 1.638-fold (CKD); 1.527 fold (Diabetes) higher in comparison with healthy cohort.

Conclusion

Our data show for the first time that TJ dysfunction in cerebral microvascular dysfunction occurs in CKD may play a role in dementia. It provides a potential mechanism for the development of CSVD in CKD patients. Our results may benefit CKD patients to reduce the following CSVD and dementia through controlling blood phosphate levels and maintain TJ’s function.

Funding

  • Private Foundation Support