Indoxyl Sulfate Induces Apoptosis through Oxidative Stress and Mitogen-Activated Protein Kinase Signaling Pathway Inhibition in Human Astrocytes

Journal of Clinical Medicine

HanYing Wang¹  Mei-Chuan Kuo²  Shang-Jyh Hwang²  Ya-Ling Hsu³  Ping-Hsun Wu⁴  Yi-Ting Lin⁴  Yi-Chun Tsai⁴  Po-Lin Kuo⁴ 

[1] Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan;Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;

关键词: indoxyl sulfate;    uremic toxins;    astrocyte;    oxidative stress;    mitogen-activated protein kinase;    dual specific phosphatase;   

DOI  :  10.3390/jcm8020191

来源: DOAJ

【 摘 要 】

Uremic toxins accumulated in chronic kidney disease (CKD) increases the risk of cognitive impairment. Indoxyl sulfate (IS) is a well-known protein-bound uremic toxin that is correlated with several systemic diseases, but no studies on human brain cells are available. We investigated the effect of IS on primary human astrocytes through next-generation sequencing and cell experiment confirmation to explore the mechanism of IS-associated brain damage. Total RNAs extracted from IS-treated and control astrocytes were evaluated by performing functional and pathway enrichment analysis. The toxicities of IS in the astrocytes were investigated in terms of cell viability through flow cytometry; the signal pathway was then investigated through immunoblotting. IS stimulated the release of reactive oxygen species, increased nuclear factor (erythroid-derived 2)-like 2 levels, and reduced mitochondrial membrane potential. IS triggered astrocyte apoptosis by inhibiting the mitogen-activated protein kinase (MAPK) pathway, including extracellular-signal-regulated kinase (ERK), MAPK/ERK kinase, c-Jun N-terminal kinase, and p38. The decreased ERK phosphorylation was mediated by the upregulated dual-specificity phosphatase 1, 5, 8, and 16. In conclusion, IS can induce neurotoxicity in patients with CKD and the pathogenesis involves cell apoptosis through oxidative stress induction and MAPK pathway inhibition in human astrocytes.

【 授权许可】

Unknown