Nasci Victoria L, Bopassa Jean C, Mironova Elena, Rhoads Megan, Singh Ravneet, Buehler Dennis P, Pollock David M, Pochynyuk Oleh M, Stockand James D, Gohar Eman Y
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States.
Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States.
Am J Physiol Renal Physiol. 2025 Jul 1;329(1):F1-F10. doi: 10.1152/ajprenal.00019.2025. Epub 2025 May 22.
Hypertension prevalence is lower in women than in men. Enhanced renal sodium (Na) handling in females has been implicated in sex differences in hypertension. Epithelial Na channel (ENaC) is a key contributor to Na homeostasis and is regulated by estrogen. Recent evidence suggests G protein-coupled estrogen receptor 1 (GPER1) evokes a female-specific natriuresis that involves endothelin-1 (ET-1). ET-1 has been shown to downregulate ENaC activity, but whether GPER1 regulates ENaC to modulate natriuresis is unknown. We tested the hypothesis that renal GPER1 functionally interacts with ENaC to promote natriuresis in a sex-specific manner. RNAscope confirmed coexpression of GPER1 and ENaC in rat renal tubules in a sex- and region-specific manner. Within the renal medulla, the number of ENaC/GPER1-positive tubules was greater in females than males. Renal medullary inhibition of ENaC or activation of GPER1 evoked comparable natriuresis in female rats. Electrophysiology revealed that pharmacological GPER1 activation downregulated ENaC activity, whereas genetic deletion of GPER1 from the principal cells of the collecting duct caused ENaC hyperactivity. The hyperactivity of ENaC caused by deletion of GPER1 in the principal cells was greater in female than male mice. RNAscope coexpression of aquaporin 2 (AQP2) and GPER1 confirmed the knockout (KO) of GPER1 from the principal cell (PC) in the kidney. Thus, renal GPER1 functionally interacts with ENaC in a sex-specific manner to promote natriuresis. This study identified GPER1 as a sex-specific upstream regulator of ENaC. We found that GPER1 and ENaC were coexpressed in the rat renal tubules in a sex and region-specific manner. Activation of GPER1 inhibited ENaC activity in isolated mouse collecting ducts, whereas deletion of GPER1 from the principal cells caused ENaC hyperactivity to a greater extent in female mice. Our data suggest GPER1 functionally interacts with ENaC in a sex-specific manner to promote natriuresis.
女性高血压患病率低于男性。女性肾脏对钠（Na）处理能力的增强与高血压的性别差异有关。上皮钠通道（ENaC）是钠稳态的关键因素，受雌激素调节。最近的证据表明，G蛋白偶联雌激素受体1（GPER1）引发了一种涉及内皮素-1（ET-1）的女性特异性利钠作用。ET-1已被证明可下调ENaC活性，但GPER1是否通过调节ENaC来调节利钠作用尚不清楚。我们检验了这样一个假设，即肾脏中的GPER1与ENaC在功能上相互作用，以性别特异性方式促进利钠作用。RNAscope技术证实了GPER1和ENaC在大鼠肾小管中以性别和区域特异性方式共表达。在肾髓质内，ENaC/GPER1阳性肾小管的数量在雌性大鼠中多于雄性大鼠。肾髓质中ENaC的抑制或GPER1的激活在雌性大鼠中引起了类似的利钠作用。电生理学研究表明，药理学上激活GPER1可下调ENaC活性，而从集合管主细胞中基因敲除GPER1则导致ENaC活性亢进。在主细胞中敲除GPER1所导致的ENaC活性亢进在雌性小鼠中比雄性小鼠更明显。RNAscope技术对水通道蛋白2（AQP2）和GPER1的共表达证实了肾脏主细胞（PC）中GPER1的敲除（KO）。因此，肾脏中的GPER1与ENaC在功能上以性别特异性方式相互作用，以促进利钠作用。本研究确定GPER1是ENaC的性别特异性上游调节因子。我们发现GPER1和ENaC在大鼠肾小管中以性别和区域特异性方式共表达。激活GPER1可抑制分离的小鼠集合管中的ENaC活性，而从主细胞中敲除GPER1在雌性小鼠中导致ENaC活性亢进的程度更大。我们的数据表明，GPER1与ENaC在功能上以性别特异性方式相互作用，以促进利钠作用。
