Indoxyl sulfate induces apoptotic cell death by inhibiting glycolysis in human astrocytes
- Author:
Seung-Hyun JEONG
1
;
Samel PARK
;
Jae-sung CHOI
;
Nam-Jun CHO
;
Jong-Seok MOON
;
Hyo-Wook GIL
Author Information
- Publication Type:Original Article
- From:Kidney Research and Clinical Practice 2024;43(6):774-784
- CountryRepublic of Korea
- Language:English
- Abstract: Neurologic complications, such as cognitive and emotional dysfunction, have frequently been observed in chronic kidney disease (CKD) patients. Previous research shows that uremic toxins play a role in the pathogenesis of CKD-associated cognitive impairment. Since astrocytes contribute to the protection and survival of neurons, astrocyte function and brain metabolism may contribute to the pathogenesis of neurodegeneration. Indoxyl sulfate (IS) is the most popular uremic toxin. However, how IS-induced astrocyte injury brings about neurologic complications in CKD patients has not been elucidated. Methods: The rate of extracellular acidification was measured in astrocytes when IS (0.5–3 mM, 4 or 7 days) treatment was applied. The hexokinase 1 (HK1), pyruvate kinase isozyme M2 (PKM2), pyruvate dehydrogenase (PDH), and phosphofructokinase (PFKP) protein levels were also measured. The activation of the apoptotic pathway was investigated using a confocal microscope, fluorescence- activated cell sorting, and cell three-dimensional imaging was used. Results: In astrocytes, IS affected glycolysis in not only dose-dependently but also time-dependently. Additionally, HK1, PKM2, PDH, and PFKP levels were decreased in IS-treated group when compared to the control. The results were prominent in cases with higher doses and longer exposure duration. The apoptotic features after IS treatment were also observed. Conclusion: Our results showed that the inhibition of glycolysis by IS in astrocytes leads to cell death via apoptosis. Specifically, longterm and higher-dose exposures had more serious effects on astrocytes. Our results suggest that the glycolysis pathway and related targets could provide a novel approach to cognitive dysfunction in CKD patients.
