title: Elimination of severe albuminuria in aging hypertensive rats by exchange of 2 chromosomes in double-consomic rats.
abstract: The inherited nephron deficit and progressive albuminuria development observed in hypertensive Munich Wistar Frömter (MWF) rats are influenced by quantitative trait loci on rat chromosome (RNO) 6 and RNO8. Previous studies in young MWF rats suggested that the nephron deficit represents a cause for glomerular hypertrophy preceding onset of albuminuria at 8 weeks and demonstrated a simultaneous induction of the podocyte stress marker desmin and podoplanin loss in podocytes. Here we investigated the separate genetic influence of RNO6 and RNO8 on early glomerular changes and subsequent albuminuria in single-consomic MWF rats in which RNO6 (MWF-6(SHR)) and RNO8 (MWF-8(SHR)) were replaced by the respective spontaneously hypertensive rat (SHR) chromosome. Furthermore, we tested the role of synergistic effects between both chromosomes in a double-consomic MWF-6(SHR)8(SHR) strain. Increased glomerular, extramesangial desmin expressions at 6 and albuminuria at 8 weeks were significantly reduced in single- and double-consomics (P<0.05 versus MWF, respectively). MWF-6(SHR)8(SHR) rats demonstrated the lowest desmin expression and glomerular volume (P<0.05 versus MWF, MWF-6(SHR), and MWF-8(SHR), respectively), indicating synergistic effects between RNO6 and RNO8. A significant and similar loss of podoplanin was only seen in MWF and MWF-6(SHR) rats but not in MWF-8(SHR) and MWF-6(SHR)8(SHR) rats (P<0.02, respectively); this refutes a mandatory coupling of desmin induction and podoplanin loss in podocytes preceding albuminuria and reveals a genetic link between RNO8 and loss of podoplanin protein. Long-term follow up in MWF-6(SHR)8(SHR) rats demonstrates the relevance of the absence of glomerular changes in young animals, because double-consomics demonstrate a complete suppression of progressive albuminuria and kidney damage compared with MWF rats despite similar blood pressures.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: van Es
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.forename: Daphne
authors.initials: D
authors.lastname: Ijpelaar
authors.forename: Annemieke
authors.initials: A
authors.lastname: van der Wal
authors.forename: Kristina
authors.initials: K
authors.lastname: Kuhn
authors.forename: Sabrina
authors.initials: S
authors.lastname: Schütten
authors.forename: Peter
authors.initials: P
authors.lastname: Kossmehl
authors.forename: Jens R
authors.initials: JR
authors.lastname: Nyengaard
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000419:Albuminuria / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D003893:Desmin / Q000235:genetics / Q000378:metabolism; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D040641:Quantitative Trait Loci; D051381:Rats
chemical_list: D003893:Desmin