Mineralocorticoid Action: Target Tissue Specificity Is Enzyme, Not Receptor, Mediated

Funder, J. W.; Pearce, P.; Smith, Robin; Smith, AI

doi:10.1126/science.2845584

Cited by 1,527 publications

(722 citation statements)

References 17 publications

Supporting

Mentioning

673

Contrasting

Unclassified

Order By: Relevance

“…HSD11B2 converts cortisol to cortisone that has apparently no relevant affinity for the MR ( Fig. 3; Funder et al 1987). Inhibition of HSD11B2 by carbenoxolone or glycyrrhetinic acid (upon consumption of large amounts of licorice) results in the unregulated occupation of MR with cortisol and, ultimately, in sodium retention, volume expansion and increases in blood pressure, accompanied by low renin activity, low aldosterone concentrations and in part a metabolic alkalosis (Stewart et al 1987).…”

Section: Apparent Mineralocortiocid Excess (Ame)mentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

View full text Add to dashboard Cite

Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

show abstract

Section: Apparent Mineralocortiocid Excess (Ame)mentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

View full text Add to dashboard Cite

show abstract

“…Flexibility and complexity in vertebrate differentiation and development also arises from temporal and tissue-specific expression of enzymes that metabolize steroids [12][13][14][15][16][17].…”

Section: Regulation Of the Steroid Response By Selective Expression Omentioning

confidence: 99%

“…I propose that the emergence in vertebrates of this ligand-based mechanism for regulating gene transcription, combined with regulation of steroid hormone access to their receptors by enzymes (Fig. 2) [12][13][14][15][16][17], was an important element in complex differentiation and development found in humans and other vertebrates. In mammals, 11β-hydroxysteroid dehydrogenase-type 1 (11β-HSD-type 1) and 11βHSD-type 2, which have less than 20% sequence identity, preferentially catalyze the reduction and oxidation of a ketone and alcohol, respectively, at C11 on glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

Evolution of adrenal and sex steroid action in vertebrates: a ligand‐based mechanism for complexity

Baker

2003

BioEssays

105

View full text Add to dashboard Cite

SummaryVarious explanations have been proposed to account for complex differentiation and development in humans, despite the human genome containing only two to three times the number of genes in invertebrates. Ignored are the actions of adrenal and sex steroids-androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins-which act through receptors that arose from an ancestral nuclear receptor in a protochordate. This ligand-based mechanism is unique to vertebrates and was integrated into the already robust network of transcription factors in invertebrates. Adrenal and sex steroids influence almost all aspects of vertebrate differentiation and development. I propose that evolution of this ligand-based mechanism in a primitive vertebrate was an important contribution to vertebrate complexity. Sequencing of genomes from a cephalochordate, such as amphioxus, and from hagfish and lamprey will establish early events in the evolution of steroid hormone signaling, and also allow genetic studies to elucidate how vertebrate complexity depends on steroid hormones.

show abstract

“…Aldosterone specificity can also be conferred to MRs by the enzyme 1 l fl-hydroxysteroid dehydrogenase (11fl-OHSD; Edwards et al, 1988;Funder et al. 1988).…”

Section: Receptor Specificity Conferring Mechanismsmentioning

confidence: 99%