Document Detail

Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats.
MedLine Citation:
PMID:  15153558     Owner:  NLM     Status:  MEDLINE    
Angiotensin II (AngII) is a critical determinant of glomerular function involving both hemodynamic and pressure-independent effects that are insufficiently understood. A novel transgenic rat (TGR) model with overexpression of the human AngII type 1 receptor (hAT1) in podocytes was developed to study the consequences of an increased AT1 signaling on the structure and function of the glomerular filter. Use of the nephrin promoter to target the podocytes resulted in an expression of the hAT1 at a level roughly two times higher than the endogenous AT1 throughout life. All male TGR developed significant albuminuria starting at 8 to 15 wk of age; systolic BP was not elevated. More or less concurrently, structural changes at the glomerulus were encountered, starting with ubiquitous formation of pseudocysts at podocytes, followed by foot process effacement and local detachments. This damage progressed to nephron loss via the well known pathway typical for classic focal segmental glomerulosclerosis. The structural changes significantly correlated with age (r(2) = 0.76) and urinary albumin excretion (r(2) = 0.70). The data provide direct evidence that increased AT1 signaling in podocytes leads to protein leakage and structural podocyte damage progressing to focal segmental glomerulosclerosis.
Sigrid Hoffmann; Dirk Podlich; Brunhilde Hähnel; Wilhelm Kriz; Norbert Gretz
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  15     ISSN:  1046-6673     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2004 Jun 
Date Detail:
Created Date:  2004-05-21     Completed Date:  2004-10-06     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1475-87     Citation Subset:  IM    
Medical Research Center, Faculty for Clinical Medicine Mannheim, University of Heidelberg, Theodor Kutzer Ufer 1-3, Haus 8, Ebene 4, Mannheim 68135, Germany.
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MeSH Terms
Albuminuria / metabolism
Animals, Genetically Modified
Blotting, Northern
Cell Membrane / metabolism
DNA, Complementary / metabolism
Dose-Response Relationship, Drug
Glomerulosclerosis, Focal Segmental / genetics,  metabolism*
In Situ Hybridization
Kidney / pathology
Kidney Glomerulus / metabolism
Kidney Tubules / metabolism
Microscopy, Electron
Microscopy, Electron, Scanning
Promoter Regions, Genetic
Protein Structure, Tertiary
RNA / metabolism
Rats, Sprague-Dawley
Receptor, Angiotensin, Type 1 / biosynthesis*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Time Factors
Tissue Distribution
Reg. No./Substance:
0/DNA, Complementary; 0/Ligands; 0/Receptor, Angiotensin, Type 1; 63231-63-0/RNA

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