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

P171 The possible involvement of androgen receptors in the development of hypertension and end-organ damage in transgenic rats harbouring the mouse Ren-2 renin gene [TGR(mREN2)27] was studied. Male TGR(mREN2)27 rats were treated with Flutamide (specific nonsteroidal competitive antagonist of the androgen receptor, 30 mg/kg/day) starting at 4 weeks of age. Blood pressure was monitored by telemetry until the establishment of hypertension (12 weeks of age). At the age of 12 weeks, urine was collected for albumin analysis (index of kidney damage). Then the rats were sacrificed and plasma angiotensinogen, renin and testosterone concentration, as well as kidney morphology were studied. Flutamide treatment produced a significant attenuation of the development of hypertension (systolic blood pressure: treated 189.7 ± 3.5 vs. control 222 ± 8 mm Hg). Heart hypertrophy was significantly reduced by the treatment (treated 0.35 ± 0.006 vs. control 0.43 ± 0.03 g/ 100 g b.w.). Urinary albumin excretion was blunted (treated 0.6 ± 0.1 vs. control 24.2 ± 7.7 mg/24 h) and no histological characteristics of end-organ damage were observed in the kidney after treatment. Flutamide treatment reduced plasma renin concentrations (treated 27.7 ± 2.7 vs. control 71.7 ± 28.5 ng/ ml), but not plasma angiotensinogen levels (treated 1.58 ± 0.1 vs. control 1.58 ± 0.1 μg/ ml). Testosterone levels increased 20 fold. Our results indicate that treatment with androgen receptor antagonist protects against end-organ damage and attenuate the hypertension in TGR(mREN2)27 rats.

Download Full-text

AT1 receptor blockade is superior to conventional triple therapy in protecting against end-organ damage in Cyp1a1-Ren-2 transgenic rats with inducible hypertension

Journal of Hypertension ◽

10.1097/01.hjh.0000251909.00923.22 ◽

2006 ◽

Vol 24 (12) ◽

pp. 2465-2472 ◽

Cited By ~ 35

Author(s):

Zdenka Vaňourková ◽

Herbert J Kramer ◽

Zuzana Husková ◽

Ivana Vaněčková ◽

Martin Opočenský ◽

...

Keyword(s):

Triple Therapy ◽

Organ Damage ◽

At1 Receptor ◽

Receptor Blockade ◽

Transgenic Rats ◽

End Organ Damage

Download Full-text

End-organ damage in hypertensive transgenic Ren-2 rats: influence of early and late endothelin receptor blockade

Physiological Research ◽

10.33549/physiolres.931640 ◽

2009 ◽

pp. S69-S78

Author(s):

Z Vernerová ◽

P Kujal ◽

HJ Kramer ◽

A Bäcker ◽

L Červenka ◽

...

Keyword(s):

Survival Rate ◽

Late Onset ◽

Severe Hypertension ◽

Organ Damage ◽

Renal Parenchyma ◽

Suitable Model ◽

Receptor Blockade ◽

End Organ Damage ◽

Selective Blockade ◽

Eta Receptor

The rat strain transgenic for the murine Ren-2 renin gene (TGR) is defined as a monogenic model of angiotensin II-dependent hypertension with endogenous activation of the renin-angiotensin system. Homozygous males TGR develop malignant hypertension with a strong salt-sensitive component. These animals show severe hypertension, proteinuria and high mortality. Morphological changes of renal parenchyma correspond to chronic ischemic glomerular changes. Heterozygous TGR develop only mild hypertension and thus provide a more suitable model of hypertension regarding to clinical studies. Within the renal parenchyma, secondary focal segmental glomerulosclerosis (FSGS) predominates. High-salt diet in heterozygous animals induces transition from benign to malignant phase of hypertension. In this case, ischemic glomerular changes are superimposed on preexisting secondary FSGS. In the regression model of hypertension (late-onset treatment) the effect of salt intake is attenuated. In homozygous TGR, early selective ETA receptor blockade decreased blood pressure and ameliorated end-organ damage. Late selective ETA receptor blockade reduced podocyte injury despite final severe hypertension. Survival rate was markedly improved in both regimens with ETA selective blockade, while there was only partial improvement with early non-selective blockade. Both bosentan and atrasentan decreased ET-1 levels in both regimens. In heterozygous TGR, early and late ETA treatment substantially while ETA/ETB treatment partially improved survival rate. Significant effect on BP was found with early and late ETA blockade, while ETA/ETB blockade had no effect. Bosentan and atrasentan similarly decreased ET-1 levels on both regimens. In conclusion, selective ETA receptor blockade is superior to nonselective ETA/ETB receptor blockade in attenuating hypertension and end-organ damage. Its effect is more pronounced when applied early in the life.

Download Full-text