Tissue-specific regulation of ACE/ACE2 and AT1/AT2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-α knock-out mice

Angiotensin-converting enzyme (ACE) and ACE2 and the AT(1) and AT(2) receptors are pivotal points of regulation in the renin-angiotensin system. ACE and ACE2 are key enzymes in the formation and degradation of angiotensin II (Ang II) and angiotensin-(1-7)(Ang-(1-7)). Ang II acts at either the AT(1) or the AT(2) receptor to mediate opposing actions of vasoconstriction or vasodilatation respectively. While it is known that oestrogen acts to downregulate ACE and the AT(1) receptor, its regulation of ACE2 and the AT(2) receptor and the involvement of a specific oestrogen receptor subtype are unknown. To investigate the role of oestrogen receptor-alpha (ER alpha) in the regulation by oestrogen of ACE/ACE2 and AT(1)/AT(2) mRNAs in lung and kidney, ovariectomized female mice lacking apolipoprotein E (ee) with the ER alpha (AAee) or without the ER alpha (alpha alpha ee) were treated with 17 beta-oestradiol (6 mu g day(-1)) or placebo for 3 months. ACE, ACE2, AT(1) receptor and AT(2) receptor mRNAs were measured using reverse transcriptase, real-time polymerase chain reaction. In the kidney, 17 beta-oestradiol showed 1.7-fold downregulation of ACE mRNA in AAee mice, with 2.1-fold upregulation of ACE mRNA in alpha alpha ee mice. 17 beta-Oestradiol showed 1.5- and 1.8-fold downregulation of ACE2 and AT(1) receptor mRNA in AAee mice; this regulation was lost in alpha alpha ee mice. 17 beta-Oestradiol showed marked (81-fold) upregulation of the AT(2) receptor mRNA in AAee mice. In the lung, 17 beta-oestradiol treatment had no effect on AT(1) receptor mRNA in AAee mice, but resulted in a 1.5-fold decreased regulation of AT(1) mRNA in alpha alpha ee mice. There was no significant interaction of oestrogen with ER alpha in the lung for ACE, ACE2 and AT(2) receptor genes. These studies reveal tissue-specific regulation by 17 beta-oestradiol of ACE/ACE2 and AT(1)/AT(2) receptor genes, with the ER alpha receptor being primarily responsible for the regulation of kidney ACE2, AT(1) receptor and AT(2) receptor genes.