Impaired brain tissue clearance in diabetic nephropathy

 

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Impaired brain tissue clearance in diabetic nephropathy

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Motoaki
Fukasawa
Motoaki Fukasawa fukamoto@fujita-hu.ac.jp Fujita Health University Biomedical Molecular Sciences Toyoake, Aichi Japan *
Shizuko Nagao shizun@fujita-hu.ac.jp Fujita Health University 2Advanced Medical Research Center of Animal Models for Human Diseases Toyoake, Aichi Japan -
Kazuo Takahashi kazuot@fujita-hu.ac.jp Fujita Health University Biomedical Molecular Sciences Toyoake, Aichi Japan -
 
 
 
 
 
 
 
 
 
 
 
 

Patients with diabetic nephropathy (DN) occasionally exhibit functional changes, such as increased irritability and an elevated risk of dementia. These clinical findings suggest that renal impairment might induce alterations within the brain. However, the specific mechanisms linking renal dysfunction to brain changes remain unclear. In this study, we investigated the effects of DN on the intracerebral environment by focusing on cerebrospinal fluid (CSF) flow dynamics and parenchymal alterations in the brain.

DN model rats were established by performing a left nephrectomy and providing 0.3% saline as drinking water for 2 weeks in diabetic SDT Fatty/Jcl rats. Behavioral characteristics were evaluated through a series of behavioral tests. To analyze CSF dynamics, a dialysis probe was inserted into the lateral ventricle, and fluorescein isothiocyanate (FITC)-labeled dextran (70 kDa; blood brain barrier-impermeant) was injected intravenously via the tail vein. CSF dialysate samples were then collected every 30min, and fluorescence intensity was quantified. FITC localization in the choroid plexus was evaluated histologically. Fluorescently labeled β-amyloid was microinjected into the striatum, and one hour later, brain sections were analyzed using fluorescence microscopy to assess the extent of dye diffusion, clearance and cellular uptake. Gene expression analysis of the choroid plexus tissue was conducted to quantify the expression of permeability-associated markers such as aquaporin-4 (AQP4) and plasmalemma vesicle-associated protein (PLVAP/ PV1).

DN rats showed more depressive behavior than diabetic rats in forced swim tests. Regarding intravenous administration of FITC-dextran, diabetic model rats exhibited a transient increase in CSF fluorescence intensity, whereas this phenomenon was absent in DN rats. Composition of the primary metabolites of the CSF significantly differed between diabetic and DN rats. FITC accumulation in the choroid plexus epithelium was significantly decreased in DN rats compared to diabetic controls. When β-amyloid was injected into the striatum, DN rats displayed greater diffusion and/or cellular uptake of the fluorophore, indicating impaired parenchymal clearance. Gene expression analysis revealed lower levels of AQP4 and PV1 expression in DN rats, highlighting reduced CSF transport and permeability. 

Our findings demonstrate that DN leads to decreased choroid plexus permeability, impaired glymphatic function, and reduced brain tissue clearance. These alterations may significantly impact the brain’s microenvironment, potentially contributing to functional deficits, including cognitive impairment and dementia observed in DN patients.

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