A new transgenic rat model overexpressing the angiotensin II type 2 receptor provides evidence for inhibition of cell proliferation in the outer adrenal cortex.
This study aimed to elucidate the role of the AT(2) receptor (AT(2)R), which is expressed and upregulated in the adrenal zona glomerulosa (ZG) under conditions of increased aldosterone production. We developed a novel transgenic rat (TGR; TGRCXmAT(2)R) that overexpresses the AT(2)R in the adrenal gland, heart, kidney, brain, skeletal muscle, testes, lung, spleen, aorta, and vein. As a consequence the total angiotensin II (Ang II) binding sites increased 7.8-fold in the kidney, 25-fold in the heart, and twofold in the adrenals. The AT(2)R number amounted to 82-98% of total Ang II binding sites. In the ZG of TGRCXmAT(2)R, the AT(2)R density was elevated threefold relative to wild-type (WT) littermates, whereas AT(1)R density remained unchanged. TGRCXmAT(2)R rats were viable and exhibited normal reproduction, blood pressure, and kidney function. Notably, a slightly but significantly reduced body weight and a moderate increase in plasma urea were observed. With respect to adrenal function, 24-h urinary and plasma aldosterone concentrations were unaffected in TGRCXmAT(2)R at baseline. Three and 14 days of Ang II infusion (300 ng·min(-1)·kg(-1)) increased plasma aldosterone levels in WT and in TGR. These changes were completely abolished by the AT(1)R blocker losartan. Of note, glomerulosa cell proliferation, as indicated by the number of Ki-67-positive glomerulosa cells, was stimulated by Ang II in TGR and WT rats; however, this increase was significantly attenuated in TGR overexpressing the AT(2)R. In conclusion, AT(2)R in the adrenal ZG inhibits Ang II-induced cell proliferation but has no obvious lasting effect on the regulation of the aldosterone production at the investigated stages.
Institute of Physiology, University of Greifswald, Karlsburg, Germany.
Barbara
B
Peters
Dirk
D
Podlich
Michael
M
Ritter
Anja
A
Müller
Heike
H
Wanka
Christiane
C
Maser-Gluth
Claudia
C
Seitz
Laura
L
de Boni
Elena
E
Maier
Norbert
N
Gretz
Jörg
J
Peters
Sigrid C
SC
Hoffmann
D000450:Aldosterone / Q000502:physiology*; D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000502:physiology; D023421:Models, Animal; D051381:Rats; D055647:Rats, Transgenic; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D015854:Up-Regulation; D015384:Zona Glomerulosa / Q000166:cytology / Q000502:physiology*
D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D000450:Aldosterone