| Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress. | |
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MedLine Citation:
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PMID: 20534867 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Uremic toxins can deteriorate renal function, but little is known about its mechanism. Because tubular injury is central to progression of chronic kidney disease (CKD), we investigated the effects of a representative uremic toxin indoxyl sulfate (IS) on tubular cells. IS induced endoplasmic reticulum (ER) stress in cultured human proximal tubular cells, demonstrated by the increase in C/EBP homologous protein (CHOP) in the immunoblots. Moreover, administration of an oral adsorbent AST-120 reduced serum IS concentration and decreased tubular expression of CHOP in immunohistochemistry in 5/6-nephretomized, CKD model, rats. Furthermore, we disclosed that IS inhibited proliferation of tubular cells in 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and 5-bromo-2'-deoxyuridine assay, whereas the results of trypan blue exclusion and lactate dehydrogenase assay showed that IS did not promote cell death. This inhibition was mitigated by small interfering (si) RNA against CHOP. Furthermore, IS increased the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) (p21). Surprisingly, this was mediated by the inflammatory cytokine interleukin (IL)-6, the expression of which was decreased by siRNA against activating transcription factor 4, another ER stress marker; however, the induction of IL-6 and p21 by IS was not suppressed by siRNA targeted to CHOP, suggesting that they were downstream of ER stress, but independent of CHOP. Moreover, we found that their upregulation was dependent on ERK, using the ERK pathway inhibitor U-0126. Collectively, we demonstrated that IS induced ER stress in tubular cells and inhibited cell proliferation via two pathways downstream of ER stress, namely CHOP and ERK-IL-6-p21. These are possible targets for suppressing progression of CKD. |
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Authors:
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Takahisa Kawakami; Reiko Inagi; Takehiko Wada; Tetsuhiro Tanaka; Toshiro Fujita; Masaomi Nangaku |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-09 |
Journal Detail:
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Title: American journal of physiology. Renal physiology Volume: 299 ISSN: 1522-1466 ISO Abbreviation: Am. J. Physiol. Renal Physiol. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-03 Completed Date: 2010-09-24 Revised Date: 2011-04-28 |
Medline Journal Info:
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Nlm Unique ID: 100901990 Medline TA: Am J Physiol Renal Physiol Country: United States |
Other Details:
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Languages: eng Pagination: F568-76 Citation Subset: IM |
Affiliation:
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University of Tokyo School of Medicine, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Carbon / pharmacology Cell Death / drug effects Cell Line Cell Proliferation / drug effects* Chronic Disease Cyclin-Dependent Kinase Inhibitor p21 / metabolism Disease Models, Animal Endoplasmic Reticulum / drug effects*, physiology Extracellular Signal-Regulated MAP Kinases / metabolism Humans Indican / pharmacology* Interleukin-6 / metabolism Kidney Diseases / metabolism Kidney Tubules, Proximal / cytology*, metabolism Male Nephrectomy Oxides / pharmacology Rats Rats, Sprague-Dawley Signal Transduction / physiology Stress, Physiological / drug effects*, physiology Transcription Factor CHOP / metabolism |
| Chemical | |
Reg. No./Substance:
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0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/DDIT3 protein, human; 0/Ddit3 protein, rat; 0/Interleukin-6; 0/Oxides; 147336-12-7/Transcription Factor CHOP; 487-94-5/Indican; 7440-44-0/Carbon; 90597-58-3/AST 120; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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