Abolition of hypertension-induced end-organ damage by androgen receptor blockade in transgenic rats harboring the mouse ren-2 gene.
A sexual dimorphism in hypertension has been observed in both human and laboratory animal studies. The mechanisms by which male sex hormones regulate cardiovascular homeostasis are still not yet fully understood and represent the subject of this study. The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harboring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with the androgen receptor antagonist Flutamide starting at 4 wk of age. Also, an androgen receptor mutation (testicular feminization mutation [tfm]) was introduced in these rats by crossbreeding male TGR(mREN2)27 rats with tfm rats. The resulting offspring male rats that contain the tfm mutation are insensitive to androgens. Flutamide treatment or tfm mutation produced a significant attenuation of the development of hypertension. Besides a reduction in cardiac hypertrophy, urinary albumin excretion was blunted and no histologic characteristics of end-organ damage were observed in the kidney after Flutamide treatment. Testosterone levels increased 15-fold after Flutamide treatment and 2.7-fold by the tfm mutation. Also, plasma estrogens and luteinizing and follicle-stimulating hormones were significantly increased. Plasma renin concentrations and activity but not plasma angiotensinogen were reduced. Our results indicate that androgens contribute not only to the development of hypertension, but even more importantly to end-organ damage in TGR(mREN2)27 rats.
Baltatu
Ovidiu
O
Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
Cayla
Cécile
C
Iliescu
Radu
R
Andreev
Dmitrii
D
Jordan
Cynthia
C
Bader
Michael
M
D000726:Androgen Antagonists / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D001794:Blood Pressure; D005260:Female; D005262:Feminization / Q000235:genetics; D005485:Flutamide / Q000494:pharmacology*; D008040:Genetic Linkage; D006066:Gonads / Q000187:drug effects / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D007668:Kidney / Q000473:pathology*; D008297:Male; D051379:Mice; D009154:Mutation / Q000502:physiology; D010902:Pituitary Gland / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology*; D014960:X Chromosome
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; C473112:Ren2 protein, mouse; D005485:Flutamide; D012083:Renin