Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, 720 20th St S, Kaul 840, Birmingham, AL, 35233, USA.
Biol Sex Differ. 2020 Sep 14;11(1):52. doi: 10.1186/s13293-020-00329-0.
Premenopausal women have a lower risk of hypertension compared to age-matched men and postmenopausal women. P2Y and P2Y purinoceptor can be considered potential contributors to hypertension due to their emerging roles in regulating renal tubular Na transport. Activation of these receptors inhibits epithelial Na channel activity (ENaC) via a phospholipase C (PLC)-dependent pathway resulting in natriuresis. We recently reported that activation of P2Y and P2Y receptors in the renal medulla by UTP promotes natriuresis in male and ovariectomized (OVX) rats, but not in ovary-intact females. This led us to hypothesize that ovary-intact females have greater basal renal medullary activity of P2 (P2Y and P2Y) receptors regulating Na excretion compared to male and OVX rats.
To test our hypothesis, we determined (i) the effect of inhibiting medullary P2 receptors by suramin (750 μg/kg/min) on urinary Na excretion in anesthetized male, ovary-intact female, and OVX Sprague Dawley rats, (ii) mRNA expression and protein abundance of P2Y and P2Y receptors, and (iii) mRNA expression of their downstream effectors (PLC-1δ and ENaCα) in renal inner medullary tissues obtained from these three groups. We also subjected cultured mouse inner medullary collecting duct cells (segment 3, mIMCD3) to different concentrations of 17ß-estradiol (E, 0, 10, 100, and 1000 nM) to test whether E increases mRNA expression of P2Y and P2Y receptors.
Acute P2 inhibition attenuated urinary Na excretion in ovary-intact females, but not in male or OVX rats. We found that P2Y and P2Y mRNA expression was higher in the inner medulla from females compared to males or OVX. Inner medullary lysates showed that ovary-intact females have higher P2Y receptor protein abundance, compared to males; however, OVX did not eliminate this sex difference. We also found that E dose-dependently upregulated P2Y and P2Y mRNA expression in mIMCD3.
These data suggest that ovary-intact females have enhanced P2Y and P2Y-dependent regulation of Na handling in the renal medulla, compared to male and OVX rats. We speculate that the P2 pathway contributes to facilitated renal Na handling in premenopausal females.
与年龄匹配的男性和绝经后女性相比，绝经前女性患高血压的风险较低。P2Y 和 P2Y 嘌呤能受体可被视为高血压的潜在致病因素，因为它们在调节肾管状钠转运方面的作用日益凸显。这些受体的激活通过磷脂酶 C（PLC）依赖性途径抑制上皮钠通道活性（ENaC），导致钠排泄增加。我们最近报道，UTP 激活肾脏髓质中的 P2Y 和 P2Y 受体可促进雄性和去卵巢（OVX）大鼠的钠排泄，但对卵巢完整的雌性没有作用。这使我们假设，与雄性和 OVX 大鼠相比，卵巢完整的雌性具有更大的基础肾脏髓质 P2（P2Y 和 P2Y）受体活性，调节钠排泄。
为了验证我们的假设，我们确定了（i）在麻醉雄性、卵巢完整的雌性和 OVX 斯普拉格道利大鼠中，通过苏拉明（750μg/kg/min）抑制髓质 P2 受体对尿钠排泄的影响，（ii）从这三组获得的肾脏内髓组织中 P2Y 和 P2Y 受体的 mRNA 表达和蛋白丰度，以及（iii）其下游效应物（PLC-1δ 和 ENaCα）的 mRNA 表达。我们还使培养的小鼠内髓集合管细胞（第 3 段，mIMCD3）接触不同浓度的 17β-雌二醇（E，0、10、100 和 1000nM），以测试 E 是否增加 P2Y 和 P2Y 受体的 mRNA 表达。
急性 P2 抑制减弱了卵巢完整雌性的尿钠排泄，但对雄性或 OVX 大鼠没有作用。我们发现，与雄性或 OVX 相比，女性内髓质中的 P2Y 和 P2Y mRNA 表达更高。内髓质裂解物显示，与雄性相比，卵巢完整的雌性具有更高的 P2Y 受体蛋白丰度；然而，OVX 并没有消除这种性别差异。我们还发现，E 剂量依赖性地上调了 mIMCD3 中的 P2Y 和 P2Y mRNA 表达。
这些数据表明，与雄性和 OVX 大鼠相比，卵巢完整的雌性具有增强的 P2Y 和 P2Y 依赖性调节肾脏髓质钠处理的能力。我们推测，P2 途径有助于绝经前女性肾脏钠处理的促进。
