Impaired Brain Tissue Clearance in Diabetic Nephropathy

Background: 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. Methods: DN model rats were established by performing a left nephrectomy and providing 0.3% saline as drinking water in diabetic SDT Fatty/Jcl rats. To analyze CSF dynamics, a dialysis probe was inserted into the lateral ventricle, and FITC-labeled dextran (70 kDa) was administered intravenously via the tail vein. CSF dialysate samples were then collected, and fluorescence intensity was measured. Additionally, 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 and cellular uptake. Gene expression analysis of the choroid plexus was conducted to quantify the expression of permeability-associated markers, such as aquaporin-4 (AQP4) and PV1. Results: Upon intravenous administration of FITC-dextran, diabetic model rats exhibited a transient increase in CSF fluorescence intensity; this effect was absent in DN rats. FITC accumulation in the choroid plexus epithelium was significantly reduced in DN rats compared to diabetic controls. Similarly, when β-amyloid was injected into the striatum, DN rats displayed greater diffusion and 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. Conclusion: 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. Funding: Government Support – Non-U.S.