Estrogen increases ENaC activity via PKCδ signaling in renal cortical collecting duct cells. Issue 5 (May 2014)

• Record Type: Journal Article
• Authors: Yusef, Yamil R.; Thomas, Warren; Harvey, Brian J.
• Is Part Of: Physiological reports. Volume 2:Issue 5(2014:May)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2014-05
• Subjects: Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.12020
• Languages: English
• ISSNs: 2051-817X

Abstract

<abstract abstract-type="main" id="phy212020-abs-0001"> <title>Abstract</title> <p>The most active estrogen, 17<italic>β</italic>‐estradiol (E2), has previously been shown to stimulate a female sex‐specific antisecretory response in the intestine. This effect is thought to contribute to the increase in whole body extracellular fluid (ECF) volume which occurs in high estrogen states, such as in the implantation window during estrous cycle. The increased ECF volume may be short‐circuited by a renal compensation unless estrogen exerts a proabsorptive effect in the nephron. Thus, the effect of E2 on ENaC in kidney cortical collecting duct (CCD) cells is of interest to understand estrogen regulation of ECF volume. Previous studies showed a rapid stimulatory effect of estrogen on ENaC in bronchial epithelium. In this study we examined if such a rapid effect on Na<sup>+</sup> absorption could occur in the kidney. Experiments were carried out on murine M1‐CCD cell cultures. E2 (25 nmol/L) treatment caused a rapid‐onset (<15 min) and sustained increase in the amiloride‐sensitive Na<sup>+</sup> current (I<sub>Na</sub>) in CCD monolayers mounted in Ussing chambers (control, 1.9 ± 0.2 <italic>μ</italic>A/cm<sup>2</sup>; E2, 4.7 ± 0.3 <italic>μ</italic>A/cm<sup>2</sup>; <italic>n</italic> = 43, <italic>P</italic> < 0.001), without affecting the ouabain‐sensitive Na<sup>+</sup>/K<sup>+</sup> pump current. The I<sub>Na</sub> response to E2 was inhibited by PKC<italic>δ</italic> activity antagonism with rottlerin (5 <italic>μ</italic>mol/L), inhibition of matrix metalloproteinases activity with GM6001 (1 <italic>μ</italic>mol/L), inhibition of EGFR activity with AG1478 (10 <italic>μ</italic>mol/L), inhibition of PLC activity with U‐73122 (10 <italic>μ</italic>mol/L), and inhibition of estrogen receptors with the general ER antagonist ICI‐182780 (100 nmol/L). The estrogen activation of I<sub>Na</sub> could be mimicked by the ER<italic>α</italic> agonist PPT (1 nmol/L). The nuclear excluded estrogen dendrimer conjugate (EDC) induced similar stimulatory effects on I<sub>Na</sub> comparable to free E2. The end target for E2 stimulation of PKC<italic>δ</italic> was shown to be an increased abundance of the <italic>γ</italic>‐ENaC subunit in the apical plasma membrane of CCD cells. We have demonstrated a novel rapid "nongenomic" function of estrogen to stimulate ENaC via ER<italic>α</italic>‐EGFR transactivation in kidney CCD cells. We propose that the salt‐retaining effect of estrogen in the kidney together with its antisecretory action in the intestine are the molecular mechanisms causing the expanded ECF volume in high‐estrogen states.</p> </abstract>