Expression of the epithelial Na+ channel and other components of an aldosterone response pathway in human adrenocortical cells

Burton, Timothy J.; Cope, Georgina; Wang, Jing; Sim, Joalice C.; Azizan, Elena; O’Shaughnessy, Kevin M.

doi:10.1016/j.ejphar.2009.04.005

Cited by 12 publications

(5 citation statements)

References 24 publications

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“…However this seems unlikely given the absence of a mineralocorticoid/glucocorticoid response element on the gene encoding for this enzyme in humans without familial hyperaldosteroneism-1 [43]. Nonetheless, the presence of MR in the adrenals [44] could lead to an indirect regulation of aldosterone synthase expression. Further studies are warranted to fully understand the mechanisms underlying the rise in aldosterone following MR antagonism.…”

Section: Discussionmentioning

confidence: 99%

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

et al. 2011

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BackgroundAccumulating evidence supports the role of the mineralocorticoid receptor (MR) in the pathogenesis of diabetic nephropathy. These findings have generated renewed interest in novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk of hyperkalemia. Characterization of novel MR antagonists warrants establishing translatable biomarkers of activity at the MR receptor. We assessed the translatability of urinary sodium to potassium ratio (Na+/K+) and plasma aldosterone as biomarkers of MR antagonism using eplerenone (Inspra®), a commercially available MR antagonist. Further we utilized these biomarkers to demonstrate antagonism of MR by PF-03882845, a novel compound.MethodsThe effect of eplerenone and PF-03882845 on urinary Na+/K+ and plasma aldosterone were characterized in Sprague-Dawley rats and spontaneously hypertensive rats (SHR). Additionally, the effect of eplerenone on these biomarkers was determined in healthy volunteers. Drug exposure-response data were modeled to evaluate the translatability of these biomarkers from rats to humans.ResultsIn Sprague-Dawley rats, eplerenone elicited a rapid effect on urinary Na+/K+ yielding an EC50 that was within 5-fold of the functional in vitro IC50. More importantly, the effect of eplerenone on urinary Na+/K+ in healthy volunteers yielded an EC50 that was within 2-fold of the EC50 generated in Sprague-Dawley rats. Similarly, the potency of PF-03882845 in elevating urinary Na+/K+ in Sprague-Dawley rats was within 3-fold of its in vitro functional potency. The effect of MR antagonism on urinary Na+/K+ was not sustained chronically; thus we studied the effect of the compounds on plasma aldosterone following chronic dosing in SHR. Modeling of drug exposure-response data for both eplerenone and PF-03882845 yielded EC50 values that were within 2-fold of that estimated from modeling of drug exposure with changes in urinary sodium and potassium excretion. Importantly, similar unbound concentrations of eplerenone in humans and SHR rats yielded the same magnitude of elevations in aldosterone, indicating a good translatability from rat to human.ConclusionsUrinary Na+/K+ and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively.Trial RegistrationFor clinical study reference EE3-96-02-004, this study was completed in 1996 and falls out scope for disclosure requirements.Clinical study reference A6141115: http://clinicaltrials.gov, http://NIHclinicaltrails.gov; NCTID: NCT00990223

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Section: Discussionmentioning

confidence: 99%

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

et al. 2011

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“…SGK1 interacts with ENaC (23) and enhances the activity of ENaC (24–32) in Xenopus oocytes (33–41), cortical collecting duct cells (42, 43), A6 cells (44–47), respiratory epithelial cells (48–50), and neurons (51). SGK1 and ENaC are further coexpressed in epithelial cells of the inner ear (52, 53) and in human adrenocortical cells (54).…”

Section: Epithelial Na+ Channel (Enac)mentioning

confidence: 99%

Regulation of ion channels by the serum‐ and glucocorticoid‐inducible kinase SGK1

2012

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The ubiquitously expressed serum- and glucocorticoid-inducible kinase-1 (SGK1) is genomically regulated by cell stress (including cell shrinkage) and several hormones (including gluco- and mineralocorticoids). SGK1 is activated by insulin and growth factors through PI3K and 3-phosphoinositide-dependent kinase PDK1. SGK1 activates a wide variety of ion channels (e.g., ENaC, SCN5A, TRPV4-6, ROMK, Kv1.3, Kv1.5, Kv4.3, KCNE1/KCNQ1, KCNQ4, ASIC1, GluR6, ClCKa/barttin, ClC2, CFTR, and Orai/STIM), which participate in the regulation of transport, hormone release, neuroexcitability, inflammation, cell proliferation, and apoptosis. SGK1-sensitive ion channels participate in the regulation of renal Na(+) retention and K(+) elimination, blood pressure, gastric acid secretion, cardiac action potential, hemostasis, and neuroexcitability. A common (∼3-5% prevalence in Caucasians and ∼10% in Africans) SGK1 gene variant is associated with increased blood pressure and body weight as well as increased prevalence of type II diabetes and stroke. SGK1 further contributes to the pathophysiology of allergy, peptic ulcer, fibrosing disease, ischemia, tumor growth, and neurodegeneration. The effect of SGK1 on channel activity is modest, and the channels do not require SGK1 for basic function. SGK1-dependent ion channel regulation may thus become pathophysiologically relevant primarily after excessive (pathological) expression. Therefore, SGK1 may be considered an attractive therapeutic target despite its broad range of functions.

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“…32 These channels are also known to exist in central nervous regions involved in BP homeostasis and have been identified as important mediators of aldosterone production in the adrenal cortex. 33-34 …”

Section: Discussionmentioning

confidence: 99%

The Epithelial Sodium Channel γ-Subunit Gene and Blood Pressure

et al. 2011

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Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in four cohorts of 1611 white European families comprising a total of 8199 individuals, we undertook staged testing of candidate SNPs for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes as well as expression of SCNN1G in human kidneys. We found that an intronic SNP of SCNN1G (rs13331086) was significantly associated with age-, sex- and BMI-adjusted blood pressure in each of the four populations (P < 0.05). In an inverse variance-weighted meta-analysis of this SNP in all four populations each additional minor allele copy was associated with a 1 mmHg increase in systolic blood pressure and 0.52 mmHg increase in diastolic blood pressure (SE = 0.33, P = 0.002 for SBP; SE = 0.21, P = 0.011 for DBP). The same allele was also associated with higher 12-h overnight urinary potassium excretion (P = 0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a non-significant (P = 0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.

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Expression of the epithelial Na+ channel and other components of an aldosterone response pathway in human adrenocortical cells

Cited by 12 publications

References 24 publications

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

The use of plasma aldosterone and urinary sodium to potassium ratio as translatable quantitative biomarkers of mineralocorticoid receptor antagonism

Regulation of ion channels by the serum‐ and glucocorticoid‐inducible kinase SGK1

The Epithelial Sodium Channel γ-Subunit Gene and Blood Pressure

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