2. Academic Validation
  3. Chronic kidney disease promotes cerebral microhemorrhage formation

Chronic kidney disease promotes cerebral microhemorrhage formation

  • J Neuroinflammation. 2023 Feb 25;20(1):51. doi: 10.1186/s12974-023-02703-2.
Chuo Fang 1,  Wei Ling Lau 2,  Jiahong Sun 3,  Rudy Chang 3,  Adrian Vallejo 1,  Donghy Lee 1,  Jihua Liu 4,  Han Liu 2,  Yu-Han Hung 1,  Yitong Zhao 2,  Annlia Paganini-Hill 1,  Rachita K Sumbria 1 3,  David H Cribbs 4,  Mark Fisher 5 6 7
Affiliations

Affiliations

  • 1 Department of Neurology, University of California, Irvine, CA, USA.
  • 2 Department of Medicine, Division of Nephrology, University of California, Irvine, CA, USA.
  • 3 Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, USA.
  • 4 Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.
  • 5 Department of Neurology, University of California, Irvine, CA, USA. mfisher@hs.uci.edu.
  • 6 Department of Pathology & Laboratory Medicine, University of California, Irvine, CA, USA. mfisher@hs.uci.edu.
  • 7 Department of Neurology, UC Irvine Medical Center, 101 The City Drive South, Shanbrom Hall (Building 55), Room 121, Orange, CA, 92868, USA. mfisher@hs.uci.edu.
PMID: 36841828 DOI: 10.1186/s12974-023-02703-2
Abstract

Background: Chronic kidney disease (CKD) is increasingly recognized as a stroke risk factor, but its exact relationship with cerebrovascular disease is not well-understood. We investigated the development of cerebral small vessel disease using in vivo and in vitro models of CKD.

Methods: CKD was produced in aged C57BL/6J mice using an adenine-induced tubulointerstitial nephritis model. We analyzed brain histology using Prussian blue staining to examine formation of cerebral microhemorrhage (CMH), the hemorrhagic component of small vessel disease and the neuropathological substrate of MRI-demonstrable cerebral microbleeds. In Cell Culture studies, we examined effects of serum from healthy or CKD patients and gut-derived uremic toxins on brain microvascular endothelial barrier.

Results: CKD was induced in aged C57BL/6J mice with significant increases in both serum creatinine and Cystatin C levels (p < 0.0001) without elevation of systolic or diastolic blood pressure. CMH was significantly increased and positively correlated with serum creatinine level (Spearman r = 0.37, p < 0.01). Moreover, CKD significantly increased Iba-1-positive immunoreactivity by 51% (p < 0.001), induced a phenotypic switch from resting to activated microglia, and enhanced fibrinogen extravasation across the blood-brain barrier (BBB) by 34% (p < 0.05). On analysis stratified by sex, the increase in CMH number was more pronounced in male mice and this correlated with greater creatinine elevation in male compared with female mice. Microglial depletion with PLX3397 diet significantly decreased CMH formation in CKD mice without affecting serum creatinine levels. Incubation of CKD serum significantly reduced transendothelial electrical resistance (TEER) (p < 0.01) and increased sodium fluorescein permeability (p < 0.05) across the endothelial monolayer. Uremic toxins (i.e., indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide) in combination with urea and lipopolysaccharide induced a marked drop in TEER compared with the control group (p < 0.0001).

Conclusions: CKD promotes the development of CMH in aged mice independent of blood pressure but directly proportional to the degree of renal impairment. These effects of CKD are likely mediated in part by microglia and are associated with BBB impairment. The latter is likely related to gut-derived bacteria-dependent toxins classically associated with CKD. Overall, these findings demonstrate an important role of CKD in the development of cerebral small vessel disease.

Keywords

Aging; Blood–brain barrier; Brain endothelial cells; Cerebral microhemorrhages/microbleeds; Chronic kidney disease; Microglial activation; Uremic toxins.

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