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Aldosterone postnatally, but not at birth, is required for optimal induction of renal mineralocorticoid receptor expression and sodium reabsorption.

ABSTRACT: Sodium wasting during the neonatal period is the consequence of a physiological aldosterone resistance, related to a low renal mineralocorticoid receptor (MR) expression at birth, both in humans and mice. To investigate whether aldosterone is involved in the neonatal regulation of MR expression, we compared aldosterone and corticosterone levels and renal MR expression by quantitative real-time PCR, between aldosterone synthase (AS) knockout, heterozygous, and wild type (WT) mice, at birth and postnatal d 8. Analysis of MR transcripts showed a similar expression profile in all genotypes, demonstrating that the lack of aldosterone does not modify either the low renal MR expression at birth or its postnatal induction. However, mRNA levels of the ?-subunit of the epithelial sodium channel, a MR target gene, were significantly higher in WT compared with AS knockout mice, both at birth and postnatal d 8, despite high corticosterone levels in AS knockout mice, indicating that aldosterone is required for optimal renal induction of the epithelial sodium channel. Using organotypic cultures of newborn WT kidneys, we confirmed that aldosterone does not regulate MR expression at birth, but is instead capable of increasing MR expression in mature kidneys, unlike dexamethasone. In sum, we demonstrate both in vivo and in vitro, that, whereas aldosterone has no significant impact on renal MR expression at birth, it is crucial for optimal MR regulation in postnatal kidneys and for appropriate hydroelectrolytic balance. Understanding of MR-regulatory mechanisms could therefore lead to new therapeutic strategies for the management of sodium loss in preterms and neonates.

SUBMITTER: Martinerie L

PROVIDER: S-EPMC3100620 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Aldosterone postnatally, but not at birth, is required for optimal induction of renal mineralocorticoid receptor expression and sodium reabsorption.

Martinerie Laetitia L Viengchareun Say S Meduri Geri G Kim Hyung-Suk HS Luther James M JM Lombès Marc M

Endocrinology 20110405 6

Sodium wasting during the neonatal period is the consequence of a physiological aldosterone resistance, related to a low renal mineralocorticoid receptor (MR) expression at birth, both in humans and mice. To investigate whether aldosterone is involved in the neonatal regulation of MR expression, we compared aldosterone and corticosterone levels and renal MR expression by quantitative real-time PCR, between aldosterone synthase (AS) knockout, heterozygous, and wild type (WT) mice, at birth and po ...[more]

PMID: 21467193

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Project description:BackgroundWhereas genome-wide association study (GWAS) has proven to be an important tool for discovery of variants influencing many human diseases and traits, unfortunately its performance has not been much of all-around success for some complex conditions, for example, hypertension. Because some of the existing effective pharmacotherapeutic agents act by targeting known biological pathways, pathway-based analytical approaches could lead to more success in discovery of disease-associated variants. The objective of the present study was to identify functional variants associated with blood pressure in the aldosterone-regulated sodium reabsorption pathway using the simulated and real blood pressure phenotypes provided for Genetic Analysis Workshop 19.MethodsThe present analysis included 1942 samples with exome sequencing data and for whom blood pressure phenotypes were available. Because only odd-numbered autosomes were available, we restricted analysis to 127 quality-controlled single-nucleotide polymorphisms from the aldosterone-regulated sodium reabsorption pathway. We performed pathway-based association analysis using appropriate regression models for single variant, haplotype and epistasis association analyses. To account for multiple comparisons, statistical significance was empirically derived by permutation procedure and Bonferroni correction.ResultsThe topmost pathway-based association signals were observed in PRKCA gene for diastolic blood pressure (DBP), systolic blood pressure (SBP), and mean arterial pressure (MAP) in both real and simulated data. The associations remained significant (P <0.05) after multiple testing corrections for the number of genes. Similarly, the pathway-based 2-locus epistasis analysis indicated significant interactions between INSR and PRKCG for SBP and MAP; INS and PIK3R2 for DBP; PIK3CD and ATP1B2 for hypertension in the real data set. We also observed significant within-gene interactions in INSR for SBP, DBP, and hypertension in the simulated data set.ConclusionThe findings from this study show that pathway-based analytical approach targeting known biological pathways can be useful in identification of disease-associated variants that are otherwise undetectable by GWAS. The approach takes advantage of the assumption of nonindependence of variants within and across pathway genes which leads to reduced penalty of multiple testing and thus less-stringent statistical significance threshold.

Project description:Accumulating 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.The 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.In 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.Urinary Na+/K+ and plasma aldosterone appear to be translatable biomarkers of MR antagonism following administration of single or multiple doses of compound, respectively.For 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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Aldosterone postnatally, but not at birth, is required for optimal induction of renal mineralocorticoid receptor expression and sodium reabsorption.

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Aldosterone postnatally, but not at birth, is required for optimal induction of renal mineralocorticoid receptor expression and sodium reabsorption.

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