Decreased 11β-Hydroxysteroid Dehydrogenase Type 2 Expression in the Kidney May Contribute to Nicotine/Smoking-Induced Blood Pressure Elevation in Mice

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.

Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease

“…11β-HSD2 catalyzes the conversion from active into inactive glucocorticoids and favors the expression and occupancy of mineralocorticoids receptors. The suppression of 11β-HSD2 by nicotine was dependent on the suppression of C/EBPβ (CCAAT/enhancer-binding protein-β) and activation of Akt protein kinase phosphorylation (pThr308Akt/PKB) by kidney cells [ 73 ]. Furthermore, exposure to oral nicotine for 28 days increased blood pressure, impaired glomerular filtration rate and fraction excretion of sodium, and augmented sympathetic cardiac modulation in mice with reduced renal Klotho gene expression [ 74 ].…”

“…Although the harmful and direct effects of nicotine are well known and reported in clinical and experimental studies ( A ), other xenobiotics released by ENDS, such as acrolein, ultrafine particles (UFP), and flavorings possess the potential to trigger deleterious effects, leading to cumulative damages and favor CKD onset ( B ), however further data are required. The direct interaction of tobacco-released compounds with the endothelium increase reactive oxygen species (ROS), decreases endothelial nitric oxide species (eNOS) [ 73 , 74 , 126 , 127 , 128 , 129 , 170 ] and leads to an inflammatory response mediated or not by nicotinic receptor activation (nAChRs) or stress sensors receptors (TRPA1) [ 75 , 123 , 124 , 125 , 146 , 147 ], evoking endothelial dysfunction, impaired vascular relaxation, and increasing blood pressure. Directly or indirectly, these xenobiotics can impair glucose metabolism by affecting β islet cell homeostasis [ 85 , 86 , 90 ] and mitochondrial function in an ROS-dependent manner, culminating in insulin resistance and Diabetes Mellitus type II onset [ 95 , 100 , 135 ].…”

US Tobacco 21 is Paving the Way for a Tobacco Endgame

“…49 (4) Nicotine products have been shown to have many detrimental effects on health, including metabolic syndrome and gut microbiota. 50,51 Ultimately following these six steps, along with other measures and programs set forth by the WHO Framework Convention on Tobacco Control (WHO FCTC), 52 will help push e-cigarettes usage on a downward trend similar to cigarette smoking. If we want this new law to effectively reduce e-cigarette usage as much as it has reduced cigarette smoking usage among both adults and youth, we must publicizeboth the data and the law itself.…”

“… 49 (4) Nicotine products have been shown to have many detrimental effects on health, including metabolic syndrome and gut microbiota. 50 , 51 …”

Potential Disruption of Systemic Hormone Transport by Tobacco Alkaloids Using Computational Approaches

“…Despite a decline of about 30% in smoking prevalence in the adult population over the last 30 years, tobacco smoking (both active and passive) continues to play havoc with as Grave's disease and goiters are also predisposed by smoking [17,21]. Smoking induces stress and increases cortisol levels in the blood and thus interferes with stress response, immunological function, and inflammatory responses [33][34][35]. Smoking during pregnancy is associated with developmental and functional problems of the fetus and in addition, predisposes the newborns to adult-onset health consequences [36].…”