Decreased 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in the Kidney May Contribute to Nicotine/Smoking-Induced Blood Pressure Elevation in Mice.
Decreased 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in the Kidney May Contribute to Nicotine/Smoking-Induced Blood Pressure Elevation in Mice.
复制标题
肾脏中11β-羟基类固醇脱氢酶2型表达降低可能导致尼古丁/吸烟诱导的小鼠血压升高。
DOI：
10.1161/hypertensionaha.120.16458
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wang Y;Wang J;Yang R;Wang P;Porche R;Kim S;Lutfy K;Liu L;Friedman TC;Jiang M;Liu Y
慢性尼古丁暴露显著增加吸烟者的高血压风险，但其潜在机制尚不清楚。在肾脏中，11β-羟基类固醇脱氢酶2型（11β-HSD 2）催化活性糖皮质激素转化为非活性糖皮质激素，并在血压调节中发挥关键作用。我们假设尼古丁诱导的血压升高部分是由肾脏11β-HSD 2的变化介导的，导致盐皮质激素受体（MR）占有率升高。在这里，我们发现尼古丁暴露显著降低了C57 BL/6 J小鼠肾脏11β-HSD 2的表达和活性，并增加了平均收缩动脉压。尼古丁降低肾脏11β-HSD 2表达与肾脏内CCAAT/增强子结合蛋白-β（C/EBPβ）的抑制和Akt蛋白激酶磷酸化（pThr 308 Akt/PKB）的激活相关。相反，尼古丁处理的小鼠肾脏MR和上皮钠通道-α（ENaCα）丰度升高。在尼古丁处理的小鼠中，MR拮抗剂螺内酯处理显著降低升高的平均收缩压和校正的ENaC沿着抑制肾脏内的pThr 308 Akt/PKB。螺内酯抑制Akt/PKB活化，同时上调肾C/EBPβ，改善尼古丁介导的11β-HSD 2减少。在小鼠肾皮质集合管M1细胞中加入尼古丁可下调11β-HSD 2并刺激MR表达，这些作用可能通过激活Akt偶联抑制C/EBPβ介导。这些结果表明，尼古丁介导的肾脏中11β-HSD 2的抑制可能通过减少肾内糖皮质激素的失活而促进尼古丁/吸烟诱导的高血压的发展。螺内酯可能被证明有助于预防尼古丁/吸烟引起的高血压风险。
Chronic nicotine exposure significantly increases hypertensive risk in smokers, but the underlying mechanisms are poorly understood. In the kidneys, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the conversion from active into inactive glucocorticoids and plays a pivotal role in the regulation of blood pressure. We hypothesized that nicotine-induced blood pressure elevation is in part mediated by change in renal 11β-HSD2 leading to higher mineralocorticoid receptor (MR) occupancy. Here, we show that nicotine exposure markedly decreased the expression and activity of renal 11β-HSD2 and increased the mean systolic arterial pressure in C57BL/6J mice. Reduction of renal 11β-HSD2 expression by nicotine was correlated with the suppression of CCAAT/enhancer binding protein-β (C/EBPβ) and activation of Akt protein kinase phosphorylation (pThr308Akt/PKB) within the kidney. Conversely, nicotine-treated mice had elevated renal MR and epithelial sodium channel-α (ENaCα) abundance. Treatment with the MR antagonist spironolactone significantly decreased the elevated mean systolic blood pressure and corrected ENaC along with inhibition of pThr308Akt/PKB within the kidney in nicotine-treated mice. Suppression of Akt/PKB activation by spironolactone was accompanied by up-regulation of renal C/EBPβ and amelioration of nicotine-mediated reduction of 11β-HSD2. Addition of nicotine to mouse renal cortical collecting duct M1 cells down-regulated 11β-HSD2 and stimulated MR expression, and these effects are likely mediated by activation of Akt coupled inhibition of C/EBPβ. These findings suggest that nicotine-mediated suppression of 11β-HSD2 in the kidney may contribute to the development of nicotine/smoking-induced hypertension through decreasing the intra-renal deactivation of glucocorticoids. Spironolactone may prove useful in protecting against the hypertensive risks of nicotine/smoking.