Decreased 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in the Kidney May Contribute to Nicotine/Smoking-Induced Blood Pressure Elevation in Mice
Ying Wang, Jian Wang, Rong Yang, Piwen Wang, Rene Porche, Samuel Kim, Kabirullah Lutfy, Limei Liu, Theodore C. Friedman, Meisheng Jiang, Yanjun Liu
Abstract
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 MR (mineralocorticoid receptor) 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 C/EBPβ (CCAAT/enhancer-binding protein-β) and activation of Akt protein kinase phosphorylation (pThr 308 Akt/PKB) within the kidney. Conversely, nicotine-treated mice had elevated renal MR and epithelial sodium channel-α abundance. Treatment with the MR antagonist spironolactone significantly decreased the elevated mean systolic blood pressure and corrected ENaC along with inhibition of pThr 308 Akt/PKB within the kidney in nicotine-treated mice. Suppression of Akt/PKB activation by spironolactone was accompanied by upregulation of renal C/EBPβ and amelioration of nicotine-mediated reduction of 11β-HSD2. Addition of nicotine to mouse renal cortical collecting duct M1 cells downregulated 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 intrarenal deactivation of glucocorticoids. Spironolactone may prove useful in protecting against the hypertensive risks of nicotine/smoking.