Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined whether transalveolar fluid transport is modulated by aldosterone in adult rats. Because colocalization of mineralocorticoid receptors (MR) with 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) is important for aldosterone specific action, we first determined the immunohistochemical distribution of MR and 11betaHSD2 in the lung. We found that alveolar epithelial cells express both MR and 11betaHSD2. Reverse transcriptase polymerase chain reaction (RT-PCR) demonstrated that rat alveolar type II epithelial cells express both MR and 11betaHSD2. We then measured alveolar fluid clearance in rats treated with chronic low-sodium diet. A low-sodium diet (0.1% NaCl for 12 to 14 days) caused hyperaldosteronism accompanied by hypokalemia, whereas serum corticosterone and adrenaline levels remained normal. We found that hyperaldosteronism was associated with significantly higher alveolar fluid clearance and that this increase was related to the amiloride-sensitive component. In addition, the increase in alveolar fluid clearance was inhibited by spironolactone. Our results show that aldosterone is able to stimulate Na+ channels of alveolar epithelial cells. We conclude that alveolar epithelium is a physiological target tissue for aldosterone and transalveolar fluid absorption could in part be modulated by endogenous aldosterone acting via MR.
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PMID:Modulation of transalveolar fluid absorption by endogenous aldosterone in adult rats. 1125 2

Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads todeleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist.
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PMID:Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1. 2620 93