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

Natriuretic peptides (NP) constitute hormonal systems of great clinical impact. This report deals with Urodilatin (URO), a renal natriuretic peptide type A. From the gene of NP type A, a message for the preprohormone is transcribed in heart and kidney. The cardiac prohormone CDD/ANP-1-126 is synthesized in the heart atrium and processed during exocytosis forming the circulating hormone CDD/ANP-99-126. URO (CDD/ANP 95-126) is a product from the same gene, but differentially processed in the kidney and detected only in urine. Physiologically, URO acts in a paracrine fashion. After release from distal tubular kidney cells into the tubular lumen, URO binds to luminal receptors (NPR-A) in the collecting duct resulting in a cGMP-dependent signal transduction. cGMP generation is followed by an interaction with the amiloriode-sensitive sodium channel which induces diuresis and natriuresis. In this way, URO physiologically regulates fluid balance and sodium homeostasis. Moreover, URO excretion and natriuresis are in turn dependent on several physiological states, such as directly by sodium homeostasis. Pharmacologically, URO at low dose administered intravenously shows a strong diuretic and natriuretic effect and a low hypotensive effect. Renal, pulmonary, and cardiovascular effects evoked by pharmacological doses indicate that URO is a putative drug for several related diseases. Clinical trials show promising results for various clinical indications. However, the reduction in hemodialysis/hemofiltration in patients suffering from ARF following heart and liver transplantation, derived from preliminary trials recruiting a small number of patients, was not confirmed by a multicenter phase II study. In contrast, data for the prophylactic use of URO in this clinical setting suggest a better outcome for the patients. Furthermore, treatment of asthmatic patients showed a convincingly beneficial effect of URO on pulmonary function. Patients with congestive heart failure may also profit from URO treatment, as it increases stroke volume and PCWP. Moreover, preliminary results from recent studies indicate that URO may also be effective in patients suffering from hepato-renal syndrome.
 ...
PMID:Urodilatin, a natriuretic peptide with clinical implications. 951 77

Patch clamp methods were used to characterize the channels on the apical membrane of initial collecting ducts from Ambystoma tigrinum. Apical membranes were exposed by everting and perfusing fragments of the renal tubule in vitro. Tubules were dissected from two groups of animals; one maintained in tap water, and the other kept in a solution of 50 mM KCl from seven to nineteen days. Patches of apical membranes on tubules taken from animals exposed to tap water expressed low-conductance amiloride sensitive sodium channels (ENaC) in 22 of 49 patches. Only three maxi K channels were observed in this group. In animals exposed to KCl, low-conductance amiloride sensitive sodium channels, 3.7 +/- 0.2 pS (36 of 45 patches) and high-conductance 98.3 +/- 5.0 pS (19 of 45 patches) potassium channels were observed. The estimated density of apical maxi K channels increased dramatically from 0.08 to 0.76 channels/mu 2 in tubules taken from animals exposed to KCl. All but four of nineteen patches which contained maxi K channels also expressed the low conductance sodium channels. Therefore, at least 85% of the maxi K channels studied were in principal cells. We speculate that the increase in maxi K channel activity may represent a mechanism for enhancing the potassium secretory capacity of the initial collecting duct. As expected, exposure of the animals to 50 mM KCl prior to dissection of the initial collecting ducts also increased the estimated density of ENaC from 0.99 to 3.89 channels/mu 2. This upregulation of sodium channel activity is presumably related to the widely recognized effect of potassium loading to increase the plasma aldosterone level.
 ...
PMID:Environmental KCl causes an upregulation of apical membrane maxi K and ENaC channels in everted Ambystoma collecting tubule. 953 4

Protons regulate electrogenic sodium absorption in a variety of epithelia, including the cortical collecting duct, frog skin, and urinary bladder. Recently, three subunits (alpha, beta, gamma) coding for the epithelial sodium channel (ENaC) were cloned. However, it is not known whether pH regulates Na+ channels directly by interacting with one of the three ENaC subunits or indirectly by interacting with a regulatory protein. As a first step to identifying the molecular mechanisms of proton-mediated regulation of apical membrane Na+ permeability in epithelia, we examined the effect of pH on the biophysical properties of ENaC. To this end, we expressed various combinations of alpha-, beta-, and gamma-subunits of ENaC in Xenopus oocytes and studied ENaC currents by the two-electrode voltage-clamp and patch-clamp techniques. In addition, the effect of pH on the alpha-ENaC subunit was examined in planar lipid bilayers. We report that alpha,beta,gamma-ENaC currents were regulated by changes in intracellular pH (pHi) but not by changes in extracellular pH (pHo). Acidification reduced and alkalization increased channel activity by a voltage-independent mechanism. Moreover, a reduction of pHi reduced single-channel open probability, reduced single-channel open time, and increased single-channel closed time without altering single-channel conductance. Acidification of the cytoplasmic solution also inhibited alpha, beta-ENaC, alpha,gamma-ENaC, and alpha-ENaC currents. We conclude that pHi but not pHo regulates ENaC and that the alpha-ENaC subunit is regulated directly by pHi.
 ...
PMID:Intracellular H+ regulates the alpha-subunit of ENaC, the epithelial Na+ channel. 995 Jul 76

The epithelial sodium channel (ENaC) plays a major role in the transepithelial reabsorption of sodium in the renal cortical collecting duct, distal colon, and lung. ENaCs are formed by three structurally related subunits, termed alpha-, beta-, and gammaENaC. We previously isolated and sequenced cDNAs encoding a portion of mouse alpha-, beta-, and gammaENaC (alpha-, beta-, and gammamENaC). These cDNAs were used to screen an oligo-dT-primed mouse kidney cDNA library. Full-length betamENaC and partial-length alpha- and gammamENaC clones were isolated. Full-length alpha- and gammamENaC cDNAs were subsequently obtained by 5'-rapid amplification of cDNA ends (5'-RACE) PCR. Injection of mouse alpha-, beta-, and gammaENaC cRNAs into Xenopus oocytes led to expression of amiloride-sensitive (K(i) = 103 nM), Na(+)-selective currents with a single-channel conductance of 4.7 pS. Northern blots revealed that alpha-, beta-, and gammamENaC were expressed in lung and kidney. Interestingly, alphamENaC was detected in liver, although transcript sizes of 9.8 kb and 3.1 kb differed in size from the 3.2-kb message observed in other tissues. A partial cDNA clone was isolated from mouse liver by 5'-RACE PCR. Its sequence was found to be nearly identical to alphamENaC. To begin to identify regions within alphamENaC that might be important in assembly of the native heteroligomeric channel, a series of functional experiments were performed using a construct of alphamENaC encoding the predicted cytoplasmic NH(2) terminus. Coinjection of wild-type alpha-, beta-, and gammamENaC with the intracellular NH(2) terminus of alphamENaC abolished amiloride-sensitive currents in Xenopus oocytes, suggesting that the NH(2) terminus of alphamENaC is involved in subunit assembly, and when present in a 10-fold excess, plays a dominant negative role in functional ENaC expression.
 ...
PMID:Cloning and functional expression of the mouse epithelial sodium channel. 1040 5

Aldosterone stimulates sodium transport in the renal collecting duct by activating the epithelial sodium channel (ENaC). To investigate the basis of this effect, we have developed a novel set of rabbit polyclonal antibodies to the 3 subunits of ENaC and have determined the abundance and distribution of ENaC subunits in the principal cells of the rat renal collecting duct. Elevated circulating aldosterone (due to either dietary NaCl restriction or aldosterone infusion) markedly increased the abundance of alphaENaC protein without increasing the abundance of the beta and gamma subunits. Thus, alphaENaC is selectively induced by aldosterone. In addition, immunofluorescence immunolocalization showed a striking redistribution in ENaC labeling to the apical region of the collecting duct principal cells. Finally, aldosterone induced a shift in molecular weight of gammaENaC from 85 kDa to 70 kDa, consistent with physiological proteolytic clipping of the extracellular loop as postulated previously. Thus, at the protein level, the response of ENaC to aldosterone stimulation is heterogenous, with both quantitative and qualitative changes that can explain observed increases in ENaC-mediated sodium transport.
 ...
PMID:Aldosterone-mediated regulation of ENaC alpha, beta, and gamma subunit proteins in rat kidney. 1051 Mar 24

The amiloride-sensitive epithelial sodium channel (ENaC) and the vasopressin-dependent water channel aquaporin-2 (AQP2) mediate mineralocorticoid-regulated sodium- and vasopressin-regulated water reabsorption, respectively. Distributions of ENaC and AQP2 have been shown by immunohistochemistry in rats. Functional data from rabbits suggest a different distribution pattern of these channels than in rats. We studied, by immunohistochemistry in the rabbit kidney cortex, the distributions of ENaC and AQP2, in conjunction with marker proteins for distal segments. In rabbit cortex ENaC is restricted to the connecting tubule (CNT) cells and cortical collecting duct (CCD) cells. The intracellular distribution of ENaC shifts from the apical membrane in the most upstream CNT cells to a cytoplasmic location further downstream in the CNT and in the CCD cells. AQP2 is detected in the CCD cells exclusively. The anatomic subdivisions in the rabbit distal nephron coincide exactly with distributions of apical transport systems. The differences between rabbits and rats in the distribution patterns of ENaC and AQP2 may explain functional differences in renal salt and water handling between these species.
 ...
PMID:Localization of epithelial sodium channel and aquaporin-2 in rabbit kidney cortex. 1075 Dec 13

Mineralocorticoids stimulate electrogenic Na+ transport in tight epithelia by altering the transcription of specific genes. Although the earliest mineralocorticoid effect is to increase the activity of the epithelial sodium channel (ENaC), ENaC mRNA and protein levels do not change. Instead, physiologic observations suggest that a mineralocorticoid target gene(s) encodes an ENaC regulator(s). To begin to identify and characterize mineralocorticoid-regulated target genes, we used suppression-subtractive hybridization to generate a cDNA library from A6 cells, a stable cell line of Xenopus laevis of distal nephron origin. A serine-threonine kinase, SGK, was identified from this screen. Sequence comparison revealed that frog, rat, and human SGK are 92% identical and 96% similar at the amino acid level. SGK mRNA was confirmed by Northern blot to be strongly and rapidly corticosteroid stimulated in A6 cells. In situ hybridization revealed that SGK was strongly stimulated by aldosterone in rat collecting duct but not proximal tubule cells. Low levels of SGK were present in rat glomeruli, but SGK was unregulated in this structure. Finally, SGK stimulated ENaC activity approximately sevenfold when coexpressed in Xenopus laevis oocytes. These data suggest that SGK is an important mediator of aldosterone effects on Na+ transport in tight epithelia. In view of the existence of SGK homologues in invertebrates, it is interesting to speculate that SGK is an ancient kinase that was adapted to the control of epithelial Na+ transport by early vertebrates as they made the transition from a marine to a freshwater environment.
 ...
PMID:Role of SGK in mineralocorticoid-regulated sodium transport. 1076 55

The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates the epithelial sodium channel. Aldosterone increases sodium reabsorption in tight epithelia. The early phase of this stimulatory effect is thought to involve activation of apical sodium channels. To identify immediate-early genes that initiate this effect, we used a combination of polymerase chain reaction-based subtractive hybridization and differential display techniques. This review summarizes our recent findings. Aldosterone rapidly increases mRNA levels of a putative Ser/Thr kinase, sgk (or serum- and glucocorticoid-regulated kinase), in the native mineralocorticoid target cells, that is, in cortical collecting duct (CCD) cells. The induction of sgk mRNA occurs within 30 minutes of the addition of aldosterone and does not require de novo protein synthesis, indicating that sgk is an immediate/early aldosterone-induced gene. Induction of sgk by aldosterone is mediated through mineralocorticoid receptors (MRs), since it is prevented by ZK91857, an MR antagonist, but not by RU486, a glucocorticoid antagonist. In addition to aldosterone, RU28362, a pure glucocorticoid receptor agonist, also induced sgk mRNA, both in primary cultures of rabbit CCD cells and in the M-1 mouse CCD cell line. Sgk mRNA levels are also influenced by changes in the osmolality of the medium. In M-1 cells, incubation of cells for one hour in a mildly hypotonic medium decreased sgk mRNA levels, whereas incubation in hypertonic medium brought about opposite changes. To determine whether sgk is involved in the regulation of the epithelial sodium channel (ENaC), we coexpressed the full-length sgk cRNA in Xenopus oocytes with the three ENaC subunits. Expression of sgk resulted in a significant increase in the amiloride-sensitive Na current, suggesting that this protein kinase plays an important role in the early phase of aldosterone-stimulated Na transport. These results indicate that sgk is an aldosterone-induced immediate/early gene in native MR target cells, and is involved in the regulation of ion transport and possibly cell volume.
 ...
PMID:The sgk, an aldosterone-induced gene in mineralocorticoid target cells, regulates the epithelial sodium channel. 1076 56

The currently available diuretics increase the urinary excretion of sodium chloride by selective inhibition of specific sodium transporters in the loop of Henle and distal nephron. In recent years, the molecular cloning of the distal diuretic-sensitive sodium transporters has improved our understanding of the cellular mechanisms of action of each class of diuretics. The identification of mutations in the genes encoding these transporters in inherited disorders characterized by altered salt balance has provided unequivocal evidence for the roles of the cloned diuretic-sensitive transporters in sodium homeostasis. The biochemical abnormalities observed in these disorders are identical to those induced by the specific diuretic. In the Guibaud-Vainsel syndrome (renal-tubular acidosis with osteopetrosis) the renal disturbances are comparable to the effects of a therapy with acetazolamide. Mutations in the proximal tubular carbonic anhydrase type II are the cause of this rare disorder. Bartter syndrome shows identical biochemical abnormalities as those found with chronic furosemide therapy. This syndrome is caused by mutations in the furosemide-sensitive Na-K-2Cl cotransporter in the thick ascending loop of Henle. In Gitelman syndrome the characteristic electrolyte and hormonal changes in blood and urine are comparable to those observed in patients treated with thiazide diuretics. This disorder results from mutations in the distal-tubular thiazide-sensitive Na-Cl cotransporter. The two forms of pseudhypoaldosteronism are distinguished by the characteristic metabolic changes encountered with a therapy with potassium-sparing diuretics. The genetic disturbance resides either in the amiloride-sensitive epithelial sodium channel (autosomal-dominant form) or in the spironolactone-sensitive mineralocorticoid receptor (autosomal-recessive form) in the distal tubule and cortical collecting duct. Current research concentrates on defining the structural sites for electrolyte transport and diuretic binding, as well as the molecular mechanisms of transport regulation. This information may allow a more appropriate use of diuretics and the design of new substances with diuretic action.
 ...
PMID:[Pharmacologic action of diuretics in the kidney]. 1089 17

Sodium transport is increased by vasopressin in the cortical collecting ducts of rats and rabbits. Here we investigate, by quantitative immunoblotting, the effects of vasopressin on abundances of the epithelial sodium channel (ENaC) subunits (alpha, beta, and gamma) in rat kidney. Seven-day infusion of 1-deamino-[8-D-arginine]-vasopressin (dDAVP) to Brattleboro rats markedly increased whole kidney abundances of beta- and gamma-ENaC (to 238% and 288% of vehicle, respectively), whereas alpha-ENaC was more modestly, yet significantly, increased (to 142% of vehicle). Similarly, 7-day water restriction in Sprague-Dawley rats resulted in significantly increased abundances of beta- and gamma- but no significant change in alpha-ENaC. Acute administration of dDAVP (2 nmol) to Brattleboro rats resulted in modest, but significant, increases in abundance for all ENaC subunits, within 1 h. In conclusion, all three subunits of ENaC are upregulated by vasopressin with temporal and regional differences. These changes are too slow to play a major role in the short-term action of vasopressin to stimulate sodium reabsorption in the collecting duct. Long-term increases in ENaC abundance should add to the short-term regulatory mechanisms (undefined in this study) to enhance sodium transport in the renal collecting duct.
 ...
PMID:Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney. 1089 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>