Decreased 11 Beta-Hydroxysteroid Dehydrogenase Type 2 Expression In The Kidney May Contribute To Nicotine/Smoking-Induced Blood Pressure Elevation In Mice

Chronic nicotine exposure significantly increases hypertensive risk in smokers, but the underlying mechanisms are poorly understood. In the kidneys, 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-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 11 beta-HSD2 leading to higher MR (mineralocorticoid receptor) occupancy. Here, we show that nicotine exposure markedly decreased the expression and activity of renal 11 beta-HSD2 and increased the mean systolic arterial pressure in C57BL/6J mice. Reduction of renal 11 beta-HSD2 expression by nicotine was correlated with the suppression of C/EBP beta (CCAAT/enhancer-binding protein-beta) 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-alpha 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/EBP beta and amelioration of nicotine-mediated reduction of 11 beta-HSD2. Addition of nicotine to mouse renal cortical collecting duct M1 cells downregulated 11 beta-HSD2 and stimulated MR expression, and these effects are likely mediated by activation of Akt coupled inhibition of C/EBP beta. These findings suggest that nicotine-mediated suppression of 11 beta-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.