Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P41181 (collecting duct)
 5,183 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aldosterone controls the activity of the amiloride-sensitive epithelial Na+ channel located in the apical membrane of epithelial cells from the distal colon and kidney collecting duct. This channel is a key element in the antinatriuretic response to aldosterone. It consists of three homologous subunits, alpha-ENaC, beta-ENaC, and gamma-ENaC (for epithelial Na+ channel), which share significant identity with degenerins, a family of proteins found in the nematode Caenorhabditis elegans, and with ligand-gated cation channels, such as FaNaC [Phe-Met-Arg-Phe-NH2 (i.e., FMRF-amide) Na+ channel] or ASIC (acid-sensing ion channel), two neuronal ionotropic receptors for Phe-Met-Arg-Phe-NH2 and H+, respectively. All of these proteins contain a large extracellular loop located between two large hydrophobic domains. The NH2- and COOH-terminal domains are cytoplasmic and contain potential regulatory motifs. Gain-of-function mutations affecting beta-ENaC and gamma-ENaC genes can cause Liddle syndrome, a rare from of genetic hypertension. Loss-of-function mutations affecting alpha-ENaC or beta-ENaC genes can cause pseudohypoaldosteronism type 1. Steroids strongly increase beta-ENaC and gamma-ENaC transcription in rat distal colon. A different situation is observed in rat kidney, in which the large stimulation of ENaC activity is mainly via posttranslational mechanisms. In both tissues, aldosterone increases cell surface expression of the ENaC subunits.
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PMID:Molecular biology of Na+ absorption. 931 61

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.
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PMID:CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity. 1094 76

In models of genetic hypertension, renal tubular dysfunction could be involved in the increased sodium and water reabsorption. However, the molecular basis for the increased renal sodium and water retention remains largely undefined in spontaneously hypertensive rats (SHR). We hypothesized that dysregulation of renal epithelial sodium channels (ENaC), sodium (co)transporters, or aquaporin-2 (AQP2) could be involved in the pathogenesis of hypertension in SHR. Six-week-old or twelve-week-old SHR and corresponding age-matched Wistar-Kyoto control rats (WKY) were studied. In both SHR groups, systolic blood pressure was markedly increased, whereas urine output, creatinine clearance, and urinary sodium excretion were decreased compared with corresponding WKY. Moreover, urine osmolality and urine-to-plasma osmolality ratio were increased compared with WKY. Semiquantitative immunoblotting demonstrated that the protein abundance of beta- and gamma-subunits of ENaC was increased in the cortex and outer stripe of the outer medulla and inner stripe of the outer medulla (ISOM) in SHR, whereas alpha-ENaC abundance was increased in ISOM. Immunoperoxidase microscopy confirmed the increased labeling of beta-ENaC and gamma-ENaC subunits in the late distal convoluted tubule, connecting tubule, and cortical and outer medullary collecting duct segments. In contrast, subcellular localization of alpha-ENaC, beta-ENaC, and gamma-ENaC was not changed. Expression of sodium/hydrogen exchanger type 3, bumetanide-sensitive Na-K-2Cl cotransporter, and thiazide-sensitive Na-Cl cotransporter was not altered in SHR. AQP2 levels were increased in the ISOM in SHR, and immunoperoxidase microscopy demonstrated an increased apical labeling of AQP2 in the inner medullary collecting duct in SHR. These results suggest that the increased protein abundance of ENaC subunits as well as the increased apical targeting of AQP2 may contribute to renal sodium and water retention observed during the development of hypertension in SHR.
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PMID:Increased expression of ENaC subunits and increased apical targeting of AQP2 in the kidneys of spontaneously hypertensive rats. 1595 75

Over 26,000 manuscripts have been published dealing with endothelins since their discovery 25 years ago. These peptides, and particularly endothelin-1 (ET-1), are expressed by, bind to, and act on virtually every cell type in the body, influencing multiple biological functions. Among these actions, the effects of ET-1 on arterial pressure and volume homeostasis have been most extensively studied. While ET-1 modulates arterial pressure through regulation of multiple organ systems, the peptide's actions in the kidney in general, and the collecting duct in particular, are of unique importance. The collecting duct produces large amounts of ET-1 that bind in an autocrine manner to endothelin A and B receptors, causing inhibition of Na(+) and water reabsorption; absence of collecting duct ET-1 or its receptors is associated with marked salt-sensitive hypertension. Collecting duct ET-1 production is stimulated by Na(+) and water loading through local mechanisms that include sensing of salt and other solute delivery as well as shear stress. Thus the collecting duct ET-1 system exists, at least in part, to detect alterations in, and maintain homeostasis for, extracellular fluid volume. Derangements in collecting duct ET-1 production may contribute to the pathogenesis of genetic hypertension. Blockade of endothelin receptors causes fluid retention due, in large part, to inhibition of the action of ET-1 in the collecting duct; this side effect has substantially limited the clinical utility of this class of drugs. Herein, the biology of the collecting duct ET-1 system is reviewed, with particular emphasis on key issues and questions that need addressing.
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PMID:Role of collecting duct endothelin in control of renal function and blood pressure. 2398 58