Rat chromosome 19 transfer from SHR ameliorates hypertension, salt-sensitivity, cardiovascular and renal organ damage in salt-sensitive Dahl rats.
OBJECTIVE
Unlike Dahl salt-sensitive (SS) rats, some strains of spontaneously hypertensive (SHR) rats develop only minor organ damage even when exposed to high-salt diet. In previous linkage studies, we identified quantitative trait loci on rat chromosome 19 (RNO19) linked to the SHR allele suggesting a protective effect against salt-induced hypertensive organ damage in SS.


METHODS
To test the relevance of this finding, we generated and characterized a consomic strain SS-19SHR in which RNO19 from SHR was introgressed into the susceptible background of SS. We compared the effects of low-salt (0.2% NaCl) and high-salt (4% NaCl) diet exposure for 8 weeks on the development of hypertension and target organ damage in male consomic and SS animals (n=14-20, each).


RESULTS
Systolic blood pressure, relative left ventricular weight and urinary protein excretion were significantly lower in SS-19SHR compared to SS under both low-salt and high-salt diet (P < 0.05, respectively). Left ventricular atrial natriuretic peptide mRNA expression showed a more pronounced 4.5-fold increase in SS compared to SS-19 (two-fold) after high-salt (P < 0.05). In comparison to low diet, high-salt exposure induced a significant increase in vascular aortic hypertrophy index, left ventricular interstitial fibrosis (+210%) and perivascular fibrosis (+195%) in SS but not in consomic SS-19SHR (P < 0.05, respectively).


CONCLUSIONS
These results demonstrate a strong protective effect of RNO19 from SHR on the development of hypertension, salt-sensitivity, cardiovascular and renal organ damage in SS. In particular, we demonstrate a genetic effect protecting against the development of cardiac fibrosis in salt-sensitive hypertension.
Wendt
Norbert
N
Institut für Klinische Pharmakologie und Toxikologie, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Schulz
Angela
A
Siegel
Anja-Kristin
AK
Weiss
Judith
J
Wehland
Markus
M
Sietmann
Anika
A
Kossmehl
Peter
P
Grimm
Daniela
D
Stoll
Monika
M
Kreutz
Reinhold
R
D000818:Animals; D001794:Blood Pressure / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000473:pathology; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D010641:Phenotype; D011507:Proteinuria / Q000235:genetics; D040641:Quantitative Trait Loci; D051381:Rats; D020303:Rats, Inbred Dahl / Q000235:genetics*; D011918:Rats, Inbred SHR / Q000235:genetics*; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D013997:Time Factors; D016277:Ventricular Function, Left / Q000235:genetics
D017673:Sodium Chloride, Dietary