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

The ATP-sensitive, inwardly rectifying K+ channel, ROMK, has been suggested to be the low-conductance ATP-sensitive K+ channel identified in apical membranes of mammalian renal thick ascending limb (TAL) and cortical collecting duct (CCD). Mutations in the human ROMK gene (KIR 1.2) have been identified in kindreds with neonatal Bartter's syndrome. In the present study, we generated polyclonal antibodies raised against both a COOH-terminal (amino acids 252-391) ROMK-maltose binding protein (MBP) fusion protein and an NH2-terminal (amino acids 34-49) ROMK peptide. Affinity-purified anti-ROMK COOH-terminal antibody detected the 45-kDa ROMK protein in kidney tissues and HEK-293 cells transfected with ROMK1 cDNA. The antibody also recognized 85- to 90-kDa proteins in kidney tissue; these higher molecular weight proteins were abolished by immunoabsorption with ROMK-MBP fusion protein and were also detected on Western blots using anti-ROMK NH2-terminal antibody. Immunofluoresence studies using anti-ROMK COOH-terminal antibody showed intense apical staining along the loop of Henle and distal nephron; staining with preimmune and immunoabsorbed serum was negative. When colocalized with distal nephron markers [the thiazide-sensitive cotransporter (rTSC1), the bumetanide-sensitive cotransporter (rBSC1), the vacuolar type H(+)-ATPase, and neuronal nitric oxide synthase (NOS I)], the ROMK protein was found primarily at the apical border of cells in the TAL, macula densa, distal convoluted tubule, and connecting tubule. Within the CCD, the ROMK protein was expressed in principal cells and was absent from intercalated cells. The tubule localization and polarity of ROMK staining are consistent with the distribution of ROMK mRNA and provide more support for ROMK being the low-conductance K+ secretory channel in the rat distal nephron.
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PMID:Localization of the ROMK protein on apical membranes of rat kidney nephron segments. 937 37

The c-Jun NH2-terminal protein kinases (JNKs), as well as the extracellular signal-regulated protein kinases (ERKs) and p38 mitogen-activated protein kinase, are activated in renal cells in response to extracellular hypertonicity. To determine whether activation of JNKs by hypertonicity is isoform-specific, renal inner medullary collecting duct cells were stably transfected with cDNA's encoding hemagglutinin (HA)-tagged JNK1 and JNK2 isoforms, and the expressed kinases were immunoprecipitated with an anti-HA antibody. Whereas both recombinant kinases were equivalently expressed, only immunoprecipitates from the HA-JNK2 cells displayed hypertonicity-inducible JNK activity. Furthermore, expression of dominant-negative JNK2 (HA-JNK2-APF) in stable clones inhibited hypertonicity-induced JNK activation by 40-70%, whereas expression of dominant-negative JNK1 (HA-JNK1-APF) had no significant inhibitory effect. Independent HA-JNK2-APF (but not HA-JNK1-APF) clones displayed greatly reduced viability relative to neomycin controls after 16 h of exposure to 600 mosM/kg hypertonic medium with percent survival of 20.5 +/- 2.7 and 31.5 +/- 7.3 for two independent HA-JNK2-APF clones compared with 80.1 +/- 1.0 for neomycin controls (p < 0.001, n = 5, mean +/- S.E.). However, neither JNK mutant blocked either regulatory volume increase or hypertonicity-induced enhancement of uptake of inositol, an organic osmolyte putatively involved in long term adaptation to hypertonicity. These results define JNK2 as the primary hypertonicity-activated JNK isoform in IMCD-3 cells and demonstrate its central importance in cellular survival in a hypertonic environment by a mechanism independent of acute regulatory volume increase as well as regulation of organic osmolyte uptake.
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PMID:Dominant-negative c-Jun NH2-terminal kinase 2 sensitizes renal inner medullary collecting duct cells to hypertonicity-induced lethality independent of organic osmolyte transport. 942 34

We have previously demonstrated that the ROMK channel maintains the property of arachidonic acid (AA) sensitivity observed originally in the native ATP-sensitive K+ channel of the rat cortical collecting duct (16). We used the patch-clamp technique to extend these studies to other NH2-terminal splice variants of the ROMK channel family, ROMK2 and ROMK3, expressed in Xenopus oocytes to determine the mechanism by which AA inhibits channel activity. Although the conductance, channel open probability, and open/closed times of the three homologs were determined to be similar, addition of 5-10 microM AA caused only a moderate inhibition of ROMK2 (15 +/- 8%) and ROMK3 (13 +/- 9%) activity, indicating that differences in the NH2 termini of ROMK channels strongly influence the AA action. We consequently examined the effect of AA on a ROMK1 variant, R1ND37, in which the NH2 terminal amino acids 2-37 were deleted, and on a mutant ROMK1, R1S4A, in which the serine-4 residue was mutated to alanine. Like ROMK2 and ROMK3, AA had a diminished effect on these variants. Addition of 1 nM exogenous protein kinase C (PKC) inhibited ROMK1 but not the mutant, R1S4A. However, the effect of AA is not a result of stimulation of a membrane bound PKC, since PKC inhibitors, calphostin C and chelerythrine, failed to abolish the AA-induced inhibition. In contrast, application of 5 microM staurosporine, a nonspecific protein kinase inhibitor at high concentration, abolished the effect of AA. We conclude that phosphorylation of serine-4 residue in the NH2 terminus plays a key role in determination of AA effect on ROMK channels.
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PMID:Role of the NH2 terminus of the cloned renal K+ channel, ROMK1, in arachidonic acid-mediated inhibition. 945 37

A mathematical model of the inner medullary collecting duct (IMCD) of the rat has been developed that is suitable for simulating luminal buffer titration and ammonia secretion by this nephron segment. Luminal proton secretion has been assigned to an H-K-ATPase, which has been represented by adapting the kinetic model of the gastric enzyme by Brzezinski et al. (P. Brzezinski, B. G. Malmstrom, P. Lorentzon, and B. Wallmark. Biochim. Biophys. Acta 942: 215-219, 1988). In shifting to a 2 H+:1 ATP stoichiometry, the model enzyme can acidify the tubule lumen approximately 3 pH units below that of the cytosol, when luminal K+ is in abundance. Peritubular base exit is a combination of ammonia recycling and HCO3- flux (either via Cl-/HCO3- exchange or via a Cl- channel). Ammonia recycling involves NH4(+) uptake on the Na-K-ATPase followed by diffusive NH3 exit [S. M. Wall. Am. J. Physiol. 270 (Renal Physiol. 39): F432-F439, 1996]; model calculations suggest that this is the principal mode of base exit. By virtue of this mechanism, the model also suggests that realistic elevations in peritubular K+ concentration will compromise IMCD acid secretion. Although ammonia recycling is insensitive to carbonic anhydrase (CA) inhibition, the base exit linked to HCO3- flux provides a CA-sensitive component to acid secretion. In model simulations, it is observed that increased luminal NaCl entry increases ammonia cycling but decreases peritubular Cl-/HCO3- exchange (due to increased cell Cl-). This parallel system of peritubular base exit stabilizes acid secretion in the face of variable Na+ reabsorption.
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PMID:A mathematical model of the inner medullary collecting duct of the rat: acid/base transport. 961 22

In cultured renal cells, hypertonicity activates multiple mitogen-activated protein kinases (MAPKs) and enhances the expression of heat shock proteins (HSPs). In rats, 24 h water restriction increased mean urinary osmolality (Uosm) from 2, 179+/-153 mOsm/kg to 2,944+/-294 mOsm/kg (P < 0.001) and was associated with significant (P < 0.05) increases in the papillary activity of c-Jun NH2-terminal protein kinase (JNK) by 22%, extracellular signal-regulated protein kinase (ERK) by 49%, and p38 MAPK by 15%. Conversely, 24 h of water-loading (Uosm 473+/-33 mOsm/kg) caused suppression of JNK activity by 43% (P < 0.001), ERK by 39% (P < 0.05), and p38 MAPK by 26% (P < 0.05). No such modulation was observed in the isotonic cortex. c-Jun phosphorylation was decreased in papilla from water-loaded rats by 45% versus controls. Expression of Hsp 110, inducible Hsp 70, and Hsp 25 was greater in the hyperosmotic papilla than the isosmotic cortex but was not affected by the animal's hydration state. In cultured inner medullary collecting duct cells, HSP expression was maximal at 500 mOsm/kg, while activation of JNK continued to increase. We conclude that under basal conditions of hydration, these HSPs are maximally expressed in the hypertonic inner medulla, while the activation of all three members of the MAPK family approaches but is not maximal.
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PMID:In vivo regulation of MAP kinases in Ratus norvegicus renal papilla by water loading and restriction. 981 74

In summary, hyperkalemia may have a dramatic impact on ammonium production and excretion. Chronic hyperkalemia decreases ammonium production in the proximal tubule and whole kidney, inhibits absorption of NH4+ in the mTALH, reduces medullary interstitial concentrations of NH4+ and NH3, and decreases entry of NH4+ and NH3 into the medullary collecting duct. The potential for development of a hyperchloremic metabolic acidosis is greatly augmented when renal insufficiency with associated reduction in functional renal mass coexists with the hyperkalemia, or in the presence of aldosterone deficiency or resistance. Such a cascade of events helps to explain, in part, the hyperchloremic metabolic acidosis and reduction in net acid excretion characteristic of several experimental models of hyperkalemic-hyperchloremic metabolic acidosis including: obstructive nephropathy, selective aldosterone deficiency, and chronic amiloride administration (7.9).
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PMID:Molecular and pathophysiologic mechanisms of hyperkalemic metabolic acidosis. 1088 37

Sustained administration of growth hormone (GH) to human subjects with NH(4)Cl-induced chronic metabolic acidosis (CMA) results in a large (4.5+/-0.5 mmol/l) increase in the plasma HCO(3-) concentration, as mediated by a large increase in renal net acid excretion. The renal mechanism(s) responsible for the potent stimulation of renal hydrogen ion secretion by GH remain to be elucidated. Accordingly, we have assessed the Na(+) dependence of prolonged GH-stimulated renal acidification in four normal NaCl-restricted subjects (Na(+) intake 0.3 mmol x kg(-1) x day(-1)) during CMA (4.2 mmol of NH(4)Cl x kg(-1) x day(-1) for 7 days), CMA plus GH (0.1 unit/kg every 12 h for 5 days) and then CMA plus GH plus NaCl (1.7 mmol x kg(-1) x day(-1) for 6 days). During CMA, urine Na(+) excretion averaged 22.4+/-4.1 mmol/24 h. In response to GH administration, urinary net acid excretion was essentially unchanged, and the accumulated increment over 5 days of GH treatment was not different from zero (14+/-12 mmol; not significant). The plasma HCO(3)(-) concentration increased only slightly, from 14.2+/-0.8 to 15.0+/-1.1 mmol/l (P<0.05). Despite the constraint on net acid excretion imposed by NaCl restriction, renal ammonia production increased, as suggested by increases in urine pH from 5.58+/-0.05 to 5.82+/-0.04 (P<0.005) and unchanged NH(4)(+) excretion (202+/-17 to 211+/-19 mmol/24 h; not significant). In response to dietary NaCl, urine pH decreased to 5.27+/-0.1 (P<0.001) and a large increment in net acid excretion accumulated (233+/-20 mmol; P<0.05), in association with an increase in plasma HCO(3-) to 18.7+/-1.3 mmol/l (P<0.001), a plasma HCO(3-) value similar to that reported previously in salt-replete, NH(4)Cl- fed subjects. These results demonstrate for the first time in any species that the acid excretory effect of GH administration is critically dependent on the availability of a surfeit of Na(+) for tubular reabsorption. GH and/or insulin-like growth factor-1 affect renal acid excretion proximally (by stimulation of NH(3) production) and by a Na(+)-transport-dependent mechanism in the collecting duct (voltage-driven acidification) in humans. The present results indicate that an isolated increase in renal NH(3) production is insufficient to obligate an increase in net acid excretion.
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PMID:On the mechanism of growth hormone-induced stimulation of renal acidification in humans: effect of dietary NaCl. 1088 57

A mathematical model of the outer medullary collecting duct (OMCD) has been developed, consisting of alpha-intercalated cells and a paracellular pathway, and which includes Na(+), K(+), Cl(-), HCO(3)(-), CO(2), H(2)CO(3), phosphate, ammonia, and urea. Proton secretion across the luminal cell membrane is mediated by both H(+)-ATPase and H-K-ATPase, with fluxes through the H-K-ATPase given by a previously developed kinetic model (Weinstein AM. Am J Physiol Renal Physiol 274: F856-F867, 1998). The flux across each ATPase is substantial, and variation in abundance of either pump can be used to control OMCD proton secretion. In comparison with the H(+)-ATPase, flux through the H-K-ATPase is relatively insensitive to changes in lumen pH, so as luminal acidification proceeds, proton secretion shifts toward this pathway. Peritubular HCO(3)(-) exit is via a conductive pathway and via the Cl(-)/HCO(3)(-) exchanger, AE1. To represent AE1, a kinetic model has been developed based on transport studies obtained at 38 degrees C in red blood cells. (Gasbjerg PK, Knauf PA, and Brahm J. J Gen Physiol 108: 565-575, 1996; Knauf PA, Gasbjerg PK, and Brahm J. J Gen Physiol 108: 577-589, 1996). Model calculations indicate that if all of the chloride entry via AE1 recycles across a peritubular chloride channel and if this channel is anything other than highly selective for chloride, then it should conduct a substantial fraction of the bicarbonate exit. Since both luminal membrane proton pumps are sensitive to small changes in cytosolic pH, variation in density of either AE1 or peritubular anion conductance can modulate OMCD proton secretory rate. With respect to the OMCD in situ, available buffer is predicted to be abundant, including delivered HCO(3)(-) and HPO(4)(2-), as well as peritubular NH(3). Thus, buffer availability is unlikely to exert a regulatory role in total proton secretion by this tubule segment.
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PMID:A mathematical model of the outer medullary collecting duct of the rat. 1089 85

For the past 50 years, the mechanism of ammonium (NH(4)(+)) transport along the collecting duct has been thought to occur through active H(+) section in parallel with the nonionic diffusion of ammonia (NH(3)). This model is supported by two basic experimental observations. First, NH(4)(+) secretion generally correlates with the NH(3) concentration gradient between the interstitium and the collecting duct lumen. This NH(3) gradient is generated through both luminal acidification, which reduces luminal NH(3) concentration, and through countercurrent multiplication, which increases interstitial NH(3) concentration. The result is secretion of NH(3) into the collecting duct lumen down its concentration gradient. Second, because NH(4)(+) permeability is low relative to that of NH(3), there is significant secretion of NH(3) into the collecting duct lumen with minimal back-diffusion of NH(4)(+). However, our laboratory, as well as others, has shown that this model is an oversimplification of the mechanism of NH(4)(+) transport along the collecting duct. NH(4)(+) is transported through a variety of K(+) transport pathways including Na,K-ATPase. K(+) and NH(4)(+) compete for a common extracellular binding site on Na, K-ATPase. During hypokalemia, interstitial K(+) concentration is reduced, which augments NH(4)(+) uptake by the Na(+) pump. In K(+) restriction, Na,K-ATPase-mediated NH(4)(+) uptake provides an important source of H(+) for net acid secretion and for the titration of luminal buffers in the terminal inner medullary collecting duct. This pathway contributes to the increase in NH(4)(+) excretion and metabolic alkalosis observed during hypokalemia.
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PMID:Impact of K(+) homeostasis on net acid secretion in rat terminal inner medullary collecting duct: role of the Na,K-ATPase. 1105 71


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