Modulation of Sel1L can alleviate altered ER homeostasis towards white matter damage in CKD-stroke complex

Area of Science:

• Neuroscience
• Nephrology
• Cellular Biology

Background:

• Stroke is a leading cause of death and disability globally.
• Chronic kidney disease (CKD) patients exhibit heightened stroke vulnerability and poorer outcomes.
• The mechanisms behind worsened stroke outcomes in CKD, particularly concerning cerebral autoregulation and white matter damage, remain unclear.

Purpose of the Study:

• To investigate the role of Sel1L-mediated endoplasmic reticulum (ER) dysfunction in exacerbating stroke outcomes in the context of CKD.
• To explore the specific contribution of altered ER homeostasis to white matter damage following stroke in CKD models.

Main Methods:

• Induction of a CKD-stroke complex in male Sprague-Dawley rats via middle-cerebral-artery occlusion.
• Behavioral assessments at 24 hours and 7 days post-reperfusion.
• Molecular studies including brain harvest and analysis of ER stress markers and Sel1L expression.

Main Results:

• CKD-stroke complex animals displayed significantly worsened neurofunctional and cognitive impairments compared to controls.
• Treatment with an ER-stress inhibitor ameliorated these deficits, indicating a key role for ER stress.
• Evidence suggests decreased Sel1L expression in CKD contributes to ER imbalance, leading to increased cell death and neurodegeneration.

Conclusions:

• Impaired ER homeostasis, driven by reduced Sel1L expression, is a critical factor in the exacerbated stroke outcomes observed in CKD.
• Targeting ER stress pathways may offer therapeutic potential for improving stroke recovery in CKD patients.