PMID- 30764571
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2077-0383 (Print)
IS  - 2077-0383 (Electronic)
IS  - 2077-0383 (Linking)
VI  - 8
IP  - 2
DP  - 2019 Feb 5
TI  - Indoxyl Sulfate Induces Apoptosis Through Oxidative Stress and Mitogen-Activated 
      Protein Kinase Signaling Pathway Inhibition in Human Astrocytes.
LID - 10.3390/jcm8020191 [doi]
LID - 191
AB  - 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.
FAU - Lin, Yi-Ting
AU  - Lin YT
AD  - Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung 807, Taiwan.
AD  - Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 
      807, Taiwan.
AD  - Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung 
      807, Taiwan.
FAU - Wu, Ping-Hsun
AU  - Wu PH
AD  - Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung 807, Taiwan.
AD  - Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 
      807, Taiwan.
AD  - Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical 
      University Hospital, Kaohsiung 807, Taiwan.
FAU - Tsai, Yi-Chun
AU  - Tsai YC
AD  - Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung 807, Taiwan.
AD  - Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 
      807, Taiwan.
AD  - Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical 
      University Hospital, Kaohsiung 807, Taiwan.
AD  - Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, 
      Kaohsiung 807, Taiwan.
FAU - Hsu, Ya-Ling
AU  - Hsu YL
AD  - Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung 807, Taiwan.
FAU - Wang, Han Ying
AU  - Wang HY
AD  - Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical 
      University Hospital, Kaohsiung 807, Taiwan.
FAU - Kuo, Mei-Chuan
AU  - Kuo MC
AD  - Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 
      807, Taiwan.
AD  - Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical 
      University Hospital, Kaohsiung 807, Taiwan.
AD  - Faculty of Renal Care, College of Medicine, Kaohsiung Medical University, 
      Kaohsiung 807, Taiwan.
FAU - Kuo, Po-Lin
AU  - Kuo PL
AD  - Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical 
      University, Kaohsiung 807, Taiwan.
FAU - Hwang, Shang-Jyh
AU  - Hwang SJ
AD  - Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 
      807, Taiwan. sjhwang@kmu.edu.tw.
AD  - Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical 
      University Hospital, Kaohsiung 807, Taiwan. sjhwang@kmu.edu.tw.
LA  - eng
GR  - MOST 106-2314-B-037-054/Ministry of Science and Technology, Taiwan/
GR  - MOST 107-2314-B-037 -098 -MY3/Ministry of Science and Technology, Taiwan/
GR  - KMUH106-6T07/Kaohsiung Medical University Chung-Ho Memorial Hospital/
GR  - KMU-DK106004/Kaohsiung Medical University/
GR  - KMU-TP104PR25/Kaohsiung Medical University/
GR  - KMU-TP105D09/Kaohsiung Medical University/
PT  - Journal Article
DEP - 20190205
PL  - Switzerland
TA  - J Clin Med
JT  - Journal of clinical medicine
JID - 101606588
PMC - PMC6406290
OTO - NOTNLM
OT  - astrocyte
OT  - dual specific phosphatase
OT  - indoxyl sulfate
OT  - mitogen-activated protein kinase
OT  - oxidative stress
OT  - uremic toxins
COIS- The authors declare no conflict of interest.
EDAT- 2019/02/16 06:00
MHDA- 2019/02/16 06:01
PMCR- 2019/02/05
CRDT- 2019/02/16 06:00
PHST- 2019/01/14 00:00 [received]
PHST- 2019/01/27 00:00 [revised]
PHST- 2019/01/31 00:00 [accepted]
PHST- 2019/02/16 06:00 [entrez]
PHST- 2019/02/16 06:00 [pubmed]
PHST- 2019/02/16 06:01 [medline]
PHST- 2019/02/05 00:00 [pmc-release]
AID - jcm8020191 [pii]
AID - jcm-08-00191 [pii]
AID - 10.3390/jcm8020191 [doi]
PST - epublish
SO  - J Clin Med. 2019 Feb 5;8(2):191. doi: 10.3390/jcm8020191.