Document Detail


Insulin receptor substrate-2 is expressed in kidney epithelium and up-regulated in diabetic nephropathy.
MedLine Citation:
PMID:  23617393     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Diabetic nephropathy (DN) is a progressive fibrotic condition that may lead to end-stage renal disease and kidney failure. Transforming growth factor-β1 and bone morphogenetic protein-7 (BMP7) have been shown to induce DN-like changes in the kidney and protect the kidney from such changes, respectively. Recent data identified insulin action at the level of the nephron as a crucial factor in the development and progression of DN. Insulin requires a family of insulin receptor substrate (IRS) proteins for its physiological effects, and many reports have highlighted the role of insulin and IRS proteins in kidney physiology and disease. Here, we observed IRS2 expression predominantly in the developing and adult kidney epithelium in mouse and human. BMP7 treatment of human kidney proximal tubule epithelial cells (HK-2 cells) increases IRS2 transcription. In addition, BMP7 treatment of HK-2 cells induces an electrophoretic shift in IRS2 migration on SDS/PAGE, and increased association with phosphatidylinositol-3-kinase, probably due to increased tyrosine/serine phosphorylation. In a cohort of DN patients with a range of chronic kidney disease severity, IRS2 mRNA levels were elevated approximately ninefold, with the majority of IRS2 staining evident in the kidney tubules in DN patients. These data show that IRS2 is expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP7 in the kidney. The specific up-regulation of IRS2 in the kidney tubules of DN patients also indicates a novel role for IRS2 as a marker and/or mediator of human DN progression.
Authors:
Michelle B Hookham; Helen C O'Donovan; Rachel H Church; Annie Mercier-Zuber; Lucilla Luzi; Simon P Curran; Rosemarie M Carew; Alejandra Droguett; Sergio Mezzano; Markus Schubert; Morris F White; John K Crean; Derek P Brazil
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-05-29
Journal Detail:
Title:  The FEBS journal     Volume:  280     ISSN:  1742-4658     ISO Abbreviation:  FEBS J.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-05     Completed Date:  2013-09-11     Revised Date:  2014-06-20    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  England    
Other Details:
Languages:  eng     Pagination:  3232-43     Citation Subset:  IM    
Copyright Information:
© 2013 FEBS.
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Animals
Base Sequence
Binding Sites
Bone Morphogenetic Protein 7 / physiology
Case-Control Studies
Cell Line
Child
Diabetic Nephropathies / metabolism*
Epithelium / metabolism
Female
Gene Expression*
Humans
Insulin Receptor Substrate Proteins / genetics,  metabolism*
Kidney Tubules / metabolism*,  pathology
Male
Mice
Middle Aged
Phosphorylation
Protein Processing, Post-Translational
Signal Transduction
Smad4 Protein / genetics
Transcriptional Activation
Young Adult
Grant Support
ID/Acronym/Agency:
R01 DK038712/DK/NIDDK NIH HHS; R01 DK098655/DK/NIDDK NIH HHS; //Biotechnology and Biological Sciences Research Council
Chemical
Reg. No./Substance:
0/BMP7 protein, human; 0/Bone Morphogenetic Protein 7; 0/IRS2 protein, human; 0/Insulin Receptor Substrate Proteins; 0/SMAD4 protein, human; 0/Smad4 Protein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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