Received December 17, 2007
Revised January 3, 2008
Accepted after revision January 3, 2008
Tissue Specific Regulation of ACE/ACE2 and AT1/AT2 Receptor Gene Expression
By Estrogen in ApoE/ERá Knock-Out Mice
K Bridget Brosnihan 1*,
Jeffrey B Hodgin 2,
Oliver Smithies 2,
Nobuyo Maeda 2,
Patricia Gallagher 3
1 Wake Forest University
2 University of North Carolina at Chapel Hill
3 Wake Forest University Health Sciences
* To whom correspondence should be addressed. E-mail: bbrosnih{at}wfubmc.edu.
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Abstract |
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ACE and ACE2 and the AT1 and AT2 receptors are pivotal points of regulation in the renin-angiotensin system. ACE and ACE2 are key enzymes in the formation and degradation of Ang II and Ang-(1-7). Ang II acts at either the AT1 or the AT2 receptor to mediate opposing actions of vasoconstriction/vasodilation. While it is known that estrogen (E2) acts to down-regulate ACE and the AT1 receptors, its regulation of ACE2 and the AT2 receptor and the involvement of a specific estrogen receptor subtype are unknown. To investigate the role of estrogen receptor-á (ERá) in estrogen's regulation of ACE/ACE2 and AT1/AT2 mRNAs in lung and kidney, ovariectomized female mice lacking apolipoprotein E (ee) with the ERá (AAee) or without the ERá (ááee) were treated with 17-â estradiol (6 µg/day) or placebo for 3 months. ACE,ACE2 and AT1/AT2 receptor mRNAs were measured using reverse transcriptase, real-time polymerase chain reaction (RT/RT-PCR). In the kidney, 17-â estradiol showed 1.7 fold down-regulation of ACE mRNA in AAee mice, with 2.1-fold up-regulation of ACE mRNA in ááee mice. 17-â estradiol showed 1.5 and 1.8 fold down-regulation of ACE2 and AT1 receptor mRNA in AAee mice; this regulation was lost in ááee mice. 17-â estradiol showed marked (81-fold) up-regulation of the AT2 receptor mRNA in AAee mice. In the lung 17-â estradiol treatment had no effect on AT1 receptor mRNA in AAee mice, but resulted in a 1.5-fold decreased regulation of AT1 mRNA in ááee. There was no significant interaction of estrogen with ER in the lung for ACE, ACE2, and AT2 receptor genes. These studies reveal tissue specific regulation by 17-â estradiol of ACE/ACE2 and AT1/AT2 receptor genes with the ERá receptor primarily responsible for the regulation of kidney ACE2 , AT1 receptor, and AT2 receptor genes.
Key Words:
Angiotensin, Gene expression, Hormones
