title: Dissecting the genetic predisposition to albuminuria and endothelial dysfunction in a genetic rat model.
abstract: OBJECTIVE
  The Munich Wistar Frömter (MWF) rat develops progressive spontaneous albuminuria largely attributable to quantitative trait loci on rat chromosome (RNO)6 and RNO8, respectively. We tested the hypothesis whether quantitative trait loci on these chromosomes are linked to both albuminuria and endothelial dysfunction.
  
  
  METHODS
  Experiments were performed in male 12-week-old MWF, Wistar Kyoto (WKY), spontaneously hypertensive rat (SHR) and consomic MWF-6 and MWF-8 rats, in which RNO6 or RNO8 was replaced by the respective SHR chromosome (n = 10 per strain). Vascular function was assessed in aorta and vascular superoxide anion production was determined by confocal microscopy.
  
  
  RESULTS
  Acetylcholine potency to induce relaxation was significantly reduced in MWF (6.2 ± 0.1) compared with WKY (7.1 ± 0.1) or SHR (7.3 ± 0.1; P < 0.01). N-nitro-L-arginine methyl ester abolished relaxation to acetylcholine in all three strains, whereas indomethacin exhibited no effect in WKY and MWF. Contractions to noradrenaline and superoxide production were significantly higher in MWF compared with SHR and WKY (P < 0.05, respectively). In consomic MWF-6 and MWF-8 rats albuminuria was markedly suppressed (-85 and -92%, P < 0.005 compared with MWF, respectively). Interestingly, relaxation to acetylcholine and contraction to noradrenaline were restored to normal WKY levels only in MWF-8, but not in MWF-6, due to an increase in stimulated and basal nitric oxide availability, respectively.
  
  
  CONCLUSIONS
  These data demonstrate the partial genetic independence of albuminuria and endothelial dysfunction in this model. From two known albuminuria quantitative trait loci one locus affects both albuminuria and endothelial dysfunction. Whether this observation is based on a common genetic mechanism related to NO availability warrants further investigation.
authors.affiliation: aInstituto Pluridisciplinar and Facultad de Farmacia, Universidad Complutense, Madrid, Spain bDepartment of Clinical Pharmacology and Toxicology, Charité - Universitätsmedizin, Berlin, Germany cDepartamento de Ciencias Farmacéuticas y de la Alimentación, Facultad de Farmacia, Universidad CEU-San Pablo dUnidad de Hipertensión. Instituto de Investigación imas12. Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Christoph
authors.initials: C
authors.lastname: Steireif
authors.forename: Concha F
authors.initials: CF
authors.lastname: García-Prieto
authors.forename: Gema
authors.initials: G
authors.lastname: Ruiz-Hurtado
authors.forename: Helena
authors.initials: H
authors.lastname: Pulido-Olmo
authors.forename: Isabel
authors.initials: I
authors.lastname: Aranguez
authors.forename: Marta
authors.initials: M
authors.lastname: Gil-Ortega
authors.forename: Beatriz
authors.initials: B
authors.lastname: Somoza
authors.forename: Gilbert
authors.initials: G
authors.lastname: Schönfelder
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.forename: Maria S
authors.initials: MS
authors.lastname: Fernández-Alfonso
authors.forename: Reinhold
authors.initials: R
authors.lastname: Kreutz
mesh_terms: D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000419:Albuminuria / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D001011:Aorta / Q000503:physiopathology; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000235:genetics; D040641:Quantitative Trait Loci; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013481:Superoxides / Q000378:metabolism; D014652:Vascular Diseases
chemical_list: D013481:Superoxides; C026512:arginine methyl ester; D009569:Nitric Oxide; D001120:Arginine; D000109:Acetylcholine; D007213:Indomethacin