Kidney Week

Abstract: SA-PO1175

Empagliflozin Attenuates CKD-Induced Cognitive Impairment by Improving Blood Brain Barrier Integrity in Mice and Endothelial Cells

Session Information

• CKD: Mechanisms - 3
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Li, Lung-Chih, Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Lung-Chih Li, MD, PhD

• Chou, Chia-An, Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Chia-An Chou, PhD

• Huang, Chiang-chi, Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Chiang-chi Huang

• Yang, Jenq-Lin, Institute for Translational Research in Biomedicine; Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Jenq-Lin Yang, PhD

Background

Chronic kidney disease (CKD) is characterized by progressive loss of renal function and complicated with varies comorbidities, including cardiovascular disorders (CVD) and neurological dysfunction. The evidence of our previous study has suggested that uremic toxins, including indoxyl sulfate (IS) and p-cresyl sulfate (PCS), could pass blood brain barrier (BBB) promoting neuroinflammation that eventually contributes to CKD-induced cognitive dysfunction. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has emerged as a novel therapeutic approach for CVD and neurodegenerative disorders. This study aims to investigate pathogenic mechanisms of CKD-induced cognitive impairment, furthermore, to determine whether EMPA improves CKD-induced neurological dysfunction.

Methods

Eight-week-old male C57B6 wide type mice received sham and 5/6 nephrectomy to mimic CKD status. EMPA was given orally for 12 weeks. The Morris water maze (MWM) testes was applied to evaluate cognitive function, including the short-term and long-term memory in shame, CKD, and EMPA-treated CKD mice. Fe³O⁴ Brain MRI and Evans blue were used to evaluate the permeability of BBB in mouse brain. Trans-well assay was used to evaluate the permeability of in vitro BBB model, constructed by bEnd3 cell, an endothelial cell from mouse brain. Western blot was used to identify the protein expression of target molecules in the brain tissue and endothelial cells.

Results

The results of in vitro study revealed that 20 μM IS, but not PCS, dysregulated permeability of brain endothelial cells (bEnd3) via disruption of tight-junction integrity. The brains of 5/6-nephrectomy-induced CKD mice also showed BBB leakage by Fe³O⁴ tail vein-injected magnetic resonant images (MRI). In addition, MWM tests indicated the impaired learning capability and long-term memory in CKD mice. The treatment of EMPA restored permeability of bEnd3 cells as well as ameliorated CKD-induced cognitive impairment that were consequences of EMPA maintaining BBB integrity of CKD mice. The evidence was demonstrated by Evans blue brain perfusion, brain MRI, MWM, and transwell permeability assay.

Conclusion

EMPA effectively improved BBB integrity and attenuated CKD-induced cognitive impairment in brains of CKD mice.

Funding

• Government Support – Non-U.S.