G protein-coupled estrogen receptor 1 regulates renal endothelin-1 signaling system in a sex-specific manner.
G protein-coupled estrogen receptor 1 regulates renal endothelin-1 signaling system in a sex-specific manner.
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DOI：
10.3389/fphys.2023.1086973
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发表时间：
2023
影响因子：
4
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中科院分区：
文献类型：
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人口统计学研究显示，绝经前女性的高血压患病率低于年龄匹配的男性。肾脏在维持钠(Na+)稳态，进而维持血压方面起着核心作用。肾内皮素-1(ET-1)是一种促钠尿肽，在血压调节和钠离子平衡方面具有性别差异。我们最近发现，肾脏延髓G蛋白偶联雌激素受体1(GPER1)的激活促进了雌性大鼠的ET-1依赖的钠尿，但对雄性大鼠没有促进作用。我们假设GPER1上调女性肾脏ET-1信号系统，但不上调男性。为了验证我们的假设，我们确定了GPER1缺失对12-16周龄雌性和雄性小鼠肾皮质、外髓和内髓中ET-1及其下游效应的影响。将GPER1基因敲除(KO)小鼠和野生型(WT)仔鼠植入遥测发射器以评估血压，并使用代谢笼测定尿钠排泄。GPER1缺失对24小时平均动脉压(MAP)和尿钠排泄均无显著影响。然而，GPER1缺失减少了女性尿液中ET-1的排泄量，但男性并非如此。值得注意的是，雌性WT小鼠的尿ET-1排泄量高于雄性WT小鼠，而在GPER1 KO小鼠中没有观察到性别差异。GPER1缺失增加了男女延髓内侧ET-1多肽的含量，但仅增加了女性延髓外侧ET-1的含量。皮质ET-1含量因GPER1缺失而增加。此外，GPER1基因缺失显著增加了雄性小鼠延髓内侧ET受体A(ETA)的表达，降低了雌性小鼠延髓外侧ET受体B(ETB)的mRNA表达。我们得出结论，GPER1是女性分泌更多ET-1所必需的。我们的数据表明，GPER1是肾脏髓质ET-1产生和ET受体表达的上游调节因子，其作用方式与性别有关。总体而言，我们的研究确定GPER1作为肾脏ET-1系统的性别特异性上游调节因子。
Demographic studies reveal lower prevalence of hypertension among premenopausal females compared to age-matched males. The kidney plays a central role in the maintenance of sodium (Na+) homeostasis and consequently blood pressure. Renal endothelin-1 (ET-1) is a pro-natriuretic peptide that contributes to sex differences in blood pressure regulation and Na+ homeostasis. We recently showed that activation of renal medullary G protein-coupled estrogen receptor 1 (GPER1) promotes ET-1-dependent natriuresis in female, but not male, rats. We hypothesized that GPER1 upregulates the renal ET-1 signaling system in females, but not males. To test our hypothesis, we determined the effect of GPER1 deletion on ET-1 and its downstream effectors in the renal cortex, outer and inner medulla obtained from 12–16-week-old female and male mice. GPER1 knockout (KO) mice and wildtype (WT) littermates were implanted with telemetry transmitters for blood pressure assessment, and we used metabolic cages to determine urinary Na+ excretion. GPER1 deletion did not significantly affect 24-h mean arterial pressure (MAP) nor urinary Na+ excretion. However, GPER1 deletion decreased urinary ET-1 excretion in females but not males. Of note, female WT mice had greater urinary ET-1 excretion than male WT littermates, whereas no sex differences were observed in GPER1 KO mice. GPER1 deletion increased inner medullary ET-1 peptide content in both sexes but increased outer medullary ET-1 content in females only. Cortical ET-1 content increased in response to GPER1 deletion in both sexes. Furthermore, GPER1 deletion notably increased inner medullary ET receptor A (ETA) and decreased outer medullary ET receptor B (ETB) mRNA expression in male, but not female, mice. We conclude that GPER1 is required for greater ET-1 excretion in females. Our data suggest that GPER1 is an upstream regulator of renal medullary ET-1 production and ET receptor expression in a sex-specific manner. Overall, our study identifies the role of GPER1 as a sex-specific upstream regulator of the renal ET-1 system.
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影响因子：
--
作者：
EDWARDS, RM;TRIZNA, W;OHLSTEIN, EH
通讯作者：
OHLSTEIN, EH
影响因子：
6.1
作者：
Gohar EY;Giachini FR;Pollock DM;Tostes RC
通讯作者：
Tostes RC
影响因子：
15.9
作者：
Ahn, D;Ge, YQ;Kohan, DE
通讯作者：
Kohan, DE
影响因子：
15.9
作者：
Chen, Z;Yuhanna, IS;Shaul, PW
通讯作者：
Shaul, PW
DOI：
10.1152/ajpregu.00267.2020
发表时间：
2021-03-01
影响因子：
2.8
作者：
Gohar, Eman Y.;Almutlaq, Rawan N.;De Miguel, Carmen
通讯作者：
De Miguel, Carmen