Document Detail


Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy.
MedLine Citation:
PMID:  16611720     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
James L Bailey; Bin Zheng; Zhaoyong Hu; S Russ Price; William E Mitch
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-04-12
Journal Detail:
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:
Created Date:  2006-04-25     Completed Date:  2006-11-02     Revised Date:  2013-10-31    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1388-94     Citation Subset:  IM    
Affiliation:
Renal Division, Emory University School of Medicine, WMB 338, 1639 Pierce Drive, Atlanta, GA 30322, USA. james.l.bailey@emory.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Cells, Cultured
Insulin / administration & dosage
Insulin-Like Growth Factor I / administration & dosage
Kidney Failure, Chronic / metabolism*
Male
Muscle, Skeletal / metabolism*
Muscular Atrophy / metabolism*
Phosphatidylinositol 3-Kinases / 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:
DK37175/DK/NIDDK NIH HHS; DK50740/DK/NIDDK NIH HHS; DK61521/DK/NIDDK NIH HHS; DK64233/DK/NIDDK NIH HHS; R37 DK037175/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Insulin; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; 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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