A new transgenic rat model overexpressing the angiotensin II type 2 receptor provides evidence for inhibition of cell proliferation in the outer adrenal cortex

摘要

This study aimed to elucidate the role of the AT_2 receptor (AT2R), 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_2R) that overexpresses the AT_2R 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_2R number amounted to 82-98% of total Ang II binding sites. In the ZG of TGRCXmAT_2R, the AT_2R density was elevated threefold relative to wild-type (WT) littermates, whereas AT_1R density remained unchanged. TGRCXmAT_2R 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_2R 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_1R 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_2R. In conclusion, AT_2R 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.