Document Detail


The Notch pathway in podocytes plays a role in the development of glomerular disease.
MedLine Citation:
PMID:  18311147     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Albuminuria associated with sclerosis of the glomerulus leads to a progressive decline in renal function affecting millions of people. Here we report that activation of the Notch pathway, which is critical in glomerular patterning, contributes to the development of glomerular disease. Expression of the intracellular domain of Notch1 (ICN1) was increased in glomerular epithelial cells in diabetic nephropathy and in focal segmental glomerulosclerosis. Conditional re-expression of ICN1 in vivo exclusively in podocytes caused proteinuria and glomerulosclerosis. In vitro and in vivo studies showed that ICN1 induced apoptosis of podocytes through the activation of p53. Genetic deletion of a Notch transcriptional partner (Rbpj) specifically in podocytes or pharmacological inhibition of the Notch pathway (with a gamma-secretase inhibitor) protected rats with proteinuric kidney diseases. Collectively, our observations suggest that Notch activation in mature podocytes is a new mechanism in the pathogenesis of glomerular disease and thus could represent a new therapeutic target.
Authors:
Thiruvur Niranjan; Bernhard Bielesz; Antje Gruenwald; Manish P Ponda; Jeffrey B Kopp; David B Thomas; Katalin Susztak
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-03-02
Journal Detail:
Title:  Nature medicine     Volume:  14     ISSN:  1546-170X     ISO Abbreviation:  Nat. Med.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-07     Completed Date:  2008-04-07     Revised Date:  2013-04-24    
Medline Journal Info:
Nlm Unique ID:  9502015     Medline TA:  Nat Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  290-8     Citation Subset:  IM    
Affiliation:
Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, New York 10461, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects,  physiology
Diabetic Nephropathies / metabolism*
Dibenzazepines / pharmacology
Female
Gene Deletion
Gene Expression Regulation
Glomerulosclerosis, Focal Segmental / metabolism*
Humans
Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics,  metabolism
Male
Mice
Mice, Transgenic
Naphthalenes
Nephrotic Syndrome / chemically induced,  drug therapy,  metabolism
Podocytes / metabolism*
Protein Structure, Tertiary
Pyridines
Rats
Receptors, Notch / antagonists & inhibitors,  genetics,  metabolism*
Transforming Growth Factor beta1 / pharmacology
Grant Support
ID/Acronym/Agency:
1R01DK076077/DK/NIDDK NIH HHS; R01 DK076077/DK/NIDDK NIH HHS; R01 DK076077-01A1/DK/NIDDK NIH HHS; R01 DK076077-02/DK/NIDDK NIH HHS; R01 DK076077-05/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Dibenzazepines; 0/Immunoglobulin J Recombination Signal Sequence-Binding Protein; 0/Naphthalenes; 0/Pyridines; 0/Receptors, Notch; 0/Transforming Growth Factor beta1; 0/dibenzazepine; 0/naphthalene-(1,2'-pyridylazo)-2-naphthol
Comments/Corrections
Comment In:
Nat Med. 2008 Mar;14(3):246-7   [PMID:  18323843 ]

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