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Tissue‐specific regulation of ACE/ACE2 and AT 1 /AT 2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor‐α knock‐out mice
Author(s) -
Brosnihan K. Bridget,
Hodgin Jeffrey B.,
Smithies Oliver,
Maeda Nobuyo,
Gallagher Patricia
Publication year - 2008
Publication title -
experimental physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.925
H-Index - 101
eISSN - 1469-445X
pISSN - 0958-0670
DOI - 10.1113/expphysiol.2007.041806
Subject(s) - downregulation and upregulation , endocrinology , medicine , angiotensin converting enzyme 2 , receptor , estrogen related receptor alpha , angiotensin ii , renin–angiotensin system , kidney , angiotensin receptor , biology , chemistry , estrogen receptor , gene , biochemistry , disease , covid-19 , cancer , breast cancer , blood pressure , infectious disease (medical specialty)
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‐α (ERα) 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 ERα ( AAee ) or without the ERα (αα ee ) were treated with 17β‐oestradiol (6 μg 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, 17β‐oestradiol showed 1.7‐fold downregulation of ACE mRNA in AAee mice, with 2.1‐fold upregulation of ACE mRNA in αα ee mice. 17β‐Oestradiol showed 1.5‐ and 1.8‐fold downregulation of ACE2 and AT 1 receptor mRNA in AAee mice; this regulation was lost in αα ee mice. 17β‐Oestradiol showed marked (81‐fold) upregulation of the AT 2 receptor mRNA in AAee mice. In the lung, 17β‐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 αα ee mice. There was no significant interaction of oestrogen with ERα in the lung for ACE, ACE2 and AT 2 receptor genes. These studies reveal tissue‐specific regulation by 17β‐oestradiol of ACE/ACE2 and AT 1 /AT 2 receptor genes, with the ERα receptor being primarily responsible for the regulation of kidney ACE2, AT 1 receptor and AT 2 receptor genes.