| Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy. | |
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MedLine Citation:
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PMID: 16611720 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Complications of chronic kidney disease (CKD) include depressed responses to insulin/IGF-1 and accelerated muscle proteolysis as a result of activation of caspase-3 and the ubiquitin-proteasome system. Experimentally, proteolysis in muscle cells occurs when there is suppression of phosphatidylinositol 3-kinase (PI3-K) activity. Postreceptor signaling through the insulin receptor substrate (IRS)/PI3-K/Akt pathway was evaluated in muscles of acidotic, CKD and pair-fed control rats under physiologic conditions and in response to a dose of insulin that quickly stimulated the pathway. Basal IRS-1-associated PI3-K activity was suppressed by CKD; IRS-2-associated PI3-K activity was increased. The basal level of activated Akt in CKD muscles also was low, indicating that the higher IRS-2-associated PI3-K activity did not compensate for the reduced IRS-1-associated PI3-K activity. Insulin treatment overcame this abnormality. The low IRS-1-associated PI3-K activity in muscle was not due to a decrease in IRS-1 protein, but there was a higher amount of the PI3-K p85 subunit protein without a concomitant increase in the p110 catalytic subunit, offering a potential explanation for the lower IRS-1-associated PI3-K activity. Eliminating the acidosis of CKD partially corrected the decrease in basal IRS-1-associated PI3-K activity and protein degradation in muscle. It is concluded that in CKD, acidosis and an increase in the PI3-K p85 subunit are mechanisms that contribute to suppression of PI3-K activity in muscle, and this leads to accelerated muscle proteolysis. |
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Authors:
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James L Bailey; Bin Zheng; Zhaoyong Hu; S Russ Price; William E Mitch |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2006-04-12 |
Journal Detail:
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Title: Journal of the American Society of Nephrology : JASN Volume: 17 ISSN: 1046-6673 ISO Abbreviation: J. Am. Soc. Nephrol. Publication Date: 2006 May |
Date Detail:
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Created Date: 2006-04-25 Completed Date: 2006-11-02 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9013836 Medline TA: J Am Soc Nephrol Country: United States |
Other Details:
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Languages: eng Pagination: 1388-94 Citation Subset: IM |
Affiliation:
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Renal Division, Emory University School of Medicine, WMB 338, 1639 Pierce Drive, Atlanta, GA 30322, USA. james.l.bailey@emory.edu |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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1-Phosphatidylinositol 3-Kinase
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metabolism* Animals Cells, Cultured Insulin / administration & dosage Insulin-Like Growth Factor I / administration & dosage Kidney Failure, Chronic / metabolism* Male Muscle, Skeletal / metabolism* Muscular Atrophy / metabolism* Proto-Oncogene Proteins c-akt / metabolism* Rats Rats, Sprague-Dawley Receptor, Insulin / metabolism* Signal Transduction / drug effects Substrate Specificity |
| Grant Support | |
ID/Acronym/Agency:
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DK37175/DK/NIDDK NIH HHS; DK50740/DK/NIDDK NIH HHS; DK61521/DK/NIDDK NIH HHS; DK64233/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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11061-68-0/Insulin; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.137/1-Phosphatidylinositol 3-Kinase; EC 2.7.10.1/Receptor, Insulin; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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