Estradiol regulates AQP2 expression in the collecting duct: a novel inhibitory role for estrogen receptor α

Abstract

While there is evidence that sex hormones influence multiple systems involved in salt and water homeostasis, the question of whether sex hormones regulate aquaporin-2 (AQP2) and thus water handling by the collecting duct has been largely ignored. Accordingly, the present study investigated AQP2 expression, localization and renal water handling in intact and ovariectomized (OVX) female rats, with and without estradiol or progesterone replacement. OVX resulted in a significant increase in urine osmolality and increase in p256-AQP2 in the renal cortex at 7 days post-OVX, as well as induced body weight changes. Relative to OVX alone, estradiol repletion produced a significant increase in urine output, normalized urinary osmolality and reduced both total AQP2 (protein and mRNA) and p256-AQP2 expression, whereas progesterone repletion had little effect. Direct effects of estradiol on AQP2 mRNA and protein levels were further tested in vitro using the mpkCCD principal cell line. Estradiol treatment of mpkCCD cells reduced AQP2 at both the mRNA and protein level in the absence of deamino-8-d-AVP (dDAVP) and significantly blunted the dDAVP-induced increase in AQP2 at the protein level only. We determined that mpkCCD and native mouse collecting ducts express both estrogen receptor (ER)α and ERβ and that female mice lacking ERα displayed significant increases in AQP2 protein compared with wild-type littermates, implicating ERα in mediating the inhibitory effect of estradiol on AQP2 expression. These findings suggest that changes in estradiol levels, such as during menopause or following reproductive surgeries, may contribute to dysregulation of water homeostasis in women.

Influence of sex on aquaporin1–4 and vasopressin V2 receptor expression in the pig kidney during development

“…This is consistent with a previous study, where they also found no sex-dependent difference in AQP2 expression in adult rats (22). It has been demonstrated that estradiol plays a role for the regulation of AQP2 in female rats subjected to ovariectomy (25). In addition, it has been shown that in human fetuses, the estradiol levels are higher in females than males (26) and moreover data has demonstrated that estradiol can lower plasma AVP levels suggesting that females might have lower AVP levels (27,28).…”

Tamoxifen attenuates development of lithium-induced nephrogenic diabetes insipidus in rats

“…Interestingly, we demonstrated that TAM attenuated AQP2 downregulation, which is likely to play a key role in lithiuminduced polyuria (20). Several studies have demonstrated a link between sex hormones and the regulation of renal AQPs (6,12). We have recently demonstrated that estradiol regulates AQP2 in kidneys from female rats subjected to ovariectomy (6).…”

“…TAM exerts its function via binding to either the membranebound ERGP or one of the nuclear ERs (ER␣ or ER␤) (4,26), and we have recently demonstrated expression of all three ER subtypes in the collecting ducts (6). TAM has either an antiestrogenic or estrogenic effect, depending on the type of tissues and cells (19).…”

“…Studies have demonstrated an important role for estrogen in regulating water and salt balance (3,28). We have recently demonstrated that estrogen affects AQP2 expression in rats subjected to ovariectomy (6). Selective estrogen receptor (ER) modulators, such as tamoxifen (TAM), have several pharmacological effects on ERs, including both agonist and antagonist actions.…”

Effects of gonadectomy and testosterone treatment on aquaporin expression in the kidney of normotensive and hypertensive rats

“…Estrogen was found to directly affect AQP expression in the kidney. 23,24 Meanwhile, testosterone has been found to up-regulate expression of AQP-4 in astrocytes 25 and AQP-1 26,27 and AQP-7 27 in uterus. In this study, AQP-2 expression in the kidney was markedly increased under testosterone influence.…”