Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene

Abstract

Abstract. 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(m-REN2)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.Men are predisposed to hypertension and cardiovascular diseases more than age-matched, premenopausal women (1). A sexual dimorphism in hypertension has been observed both in human and laboratory animal studies (2). The mechanisms responsible for the gender differences in BP control are not yet clear and continue to be subject of active investigation (3). Evidence is accumulating that androgens may play an important role in gender-associated differences in BP regulation. Several studies have indicated that androgens may mediate hypertension and renal injury (4 -8). However, the mechanisms by which male sex hormones regulate cardiovascular homeostasis are not yet fully understood (3) and represent the subject of this study. There are indications for an interrelation between androgens and the renin-angiotensin system (RAS) (3); therefore, we studied the consequences of androgen receptor blockade on the development of malignant hypertension in transgenic TGR(mREN2)27 rats with overactive RAS (9,10). Androgen receptor inhibition was achieved by treatment with the antagonist Flutamide or by introducing a testicular feminization mutation (tfm) mutation, and BP as well as end-organ damage and RAS and pituitary-gonadal hormones were evaluated. Materials and Methods Rat StrainsMale transgenic heterozygous rats [TGR(mREN2)27] (n ϭ 24 rats) were obtained from the animal facilities of the Max-Delbrück-Center for Molecular Medicine, Berlin, Germany. Female Long-Evans rats carrying the X-linked rece...

Development of Focal Segmental Glomerulosclerosis after Anabolic Steroid Abuse

“…31,32 An animal model of hypertension-induced end-organ damage showed significant attenuation of renal damage by androgen receptor blockade with flutamide. 33 In uninephrectomy models, male rats developed greater proteinuria and mesangial sclerosis than did female rats. 34 Testosterone seems to amplify compensatory glomerular and tubular growth, which may promote glomerulosclerosis.…”

Sex differences in circulating and renal angiotensins of hypertensive mRen().Lewis but not normotensive Lewis rats

“…Estrogen is known to downregulate both ACE and the AT 1 receptor, as well as increase the expression of the AT 2 receptor and ACE2, which may further attenuate the actions of the ACE-ANG II-AT 1 axis (3,10,17,27,33,56,59). In contrast, testosterone may increase ACE and the AT 1 receptor as well as angiotensinogen (9,27). To our knowledge, the current studies are the first to document the sex-based differential expression of both circulating and tissue ANG II and ANG-(1-7) in any hypertensive strain.…”

“…Indeed, the cardioprotective effects of estrogen replacement in mRen (2).Lewis rats, an ANG IIdependent model of hypertension, are consistent with its actions to directly attenuate key components of the RAAS, including angiotensin-converting enzyme (ACE) and the AT 1 receptor (12,40,45), as well as the increase of competing components such as ACE2 and the ANG II type 2 (AT 2 ) receptor or influence other signaling pathways (nitric oxide and prostaglandins) that may converge on the RAAS (3,11,41,60,65). Androgens, however, may also have a significant effect on cardiovascular regulation to increase blood pressure and accelerate renal injury that is associated with alterations of the RAAS, including the increased expression of renin, angiotensinogen, and ACE (6,8,9,47). Furthermore, estrogen may exhibit additional effects on the RAAS, including the stimulation of renin and angiotensinogen that in some instances may promote an increase in blood pressure (12).…”

Genetic modifiers of hypertension in soluble guanylate cyclase α1–deficient mice

“…For example, renin 2 was reported to be an androgen-responsive gene (66,67). Moreover, overexpression of murine renin 2 in rats resulted in testosteronedependent hypertension (68). Furthermore, the RAAS has been suggested to have a greater impact on blood pressure regulation in males than in females: knocking out the gene encoding ACE1 decreased blood pressure in male but not female mice (69), and in a large population study, genetic linkage of the ACE locus with hypertension was found in men but not in women (70).…”