Elevated blood pressure and heart rate in human renin receptor transgenic rats.
Recently, a receptor for renin was described that may be important for vascular uptake and activation of (pro)renin, thus leading to local generation of angiotensin II. To assess the in vivo relevance of this protein, we generated transgenic rats overexpressing the human renin receptor gene in smooth muscle tissue, under the control of a 16-kb fragment of the mouse smooth muscle myosin heavy chain gene [TGR(SMMHC-HRR)]. Four lines of transgenic animals were obtained. The correct pattern of expression of the transgene was confirmed by RNase protection assay and in situ hybridization. TGR(SMMHC-HRR) rats are fertile and develop normally. After 6 months of age, transgenic rats develop a cardiovascular phenotype with an elevated systolic blood pressure (137.8+/-5 versus 118.9+/-3.7 mm Hg; P=0.008), and an augmentation in heart rate (349.1+/-7.7 versus 303.1+/-16.16 bpm; P=0.023) in TGR(SMMHC-HRR) and controls, respectively. These alterations are progressively increasing with aging. Although kidney function and plasma renin were normal in TGR(SMMHC-HRR), an increase in plasma aldosterone [TGR(SMMHC-HRR) 428+/-64.9 versus 207.3+/-73.24 pg/mL in control; P=0.02] and in aldosterone/renin ratio [TGR(SMMHC-HRR) 8.04+/-2.2 versus 2.8+/-0.55 in control; P=0.03] was observed. This suggests that renin receptor overexpression has resulted in increased intraadrenal angiotensin II, thereby provoking enhanced aldosterone generation in the absence of changes in plasma renin. The rise in aldosterone may underlie, at least in part, the observed cardiovascular phenotype of TGR(SMMHC-HRR).
Burcklé
Céline A
CA
Inserm U36, Paris, France.
Jan Danser
A H
AH
Müller
Dominik N
DN
Garrelds
Ingrid M
IM
Gasc
Jean-Marie
JM
Popova
Elena
E
Plehm
Ralph
R
Peters
Jörg
J
Bader
Michael
M
Nguyen
Geneviève
G
D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001158:Arteries / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology*; D002320:Cardiovascular Physiological Phenomena; D015870:Gene Expression; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics; D010641:Phenotype; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System; D019076:Transgenes
D011956:Receptors, Cell Surface; D000450:Aldosterone; D012083:Renin; D018995:Myosin Heavy Chains