Effect of estrogen on neprilysin expression in uterus and kidney of Sprague-Dawley normotensive and heterozygous (mRen2)27-transgenic hypertensive rats.
The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague-Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17beta-estradiol (E2). We evaluated estrogen's influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1-7) [Ang-(1-7)] and on aminopeptidase (AMP), which degrades Ang-(1-7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31+/-0.03 nmol/min/mg versus 0.18+/-0.04 nmol/min/mg of protein, p<0.05) and Tg(+) (0.26+/-0.04 nmol/min/mg versus 0.13+/-0.02 nmol/min/mg of protein, p<0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female (p<0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1-7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent.
Neves
L A A
LA
The Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1932, USA.
Chappell
M C
MC
Ferrario
C M
CM
Gallagher
P E
PE
Ganten
D
D
Brosnihan
K B
KB
D000626:Aminopeptidases / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001794:Blood Pressure / Q000187:drug effects; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006579:Heterozygote; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D010052:Ovariectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D012083:Renin / Q000235:genetics*; D012727:Sex Characteristics; D014599:Uterus / Q000187:drug effects / Q000378:metabolism*
D004967:Estrogens; D012333:RNA, Messenger; C473112:Ren2 protein, mouse; D000626:Aminopeptidases; D012083:Renin; D015260:Neprilysin