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)

The activity of apical K(+) channels in cortical collecting duct (CCD) is stimulated and inhibited by protein kinase A (PKA) and C (PKC), respectively. Direct interaction between phosphatidylinositol 4,5-bisphosphate (PIP(2)) and the cloned CCD K(+) channel, ROMK1, is critical for channel opening. We have found previously that phosphorylation of ROMK1 by PKA increases affinity of the channel for PIP(2) and mutation of PKA sites reduces the affinity of ROMK1 for PIP(2). In this study we investigate the molecular mechanism for PKC regulation of ROMK and report that mutants of ROMK1 with reduced PIP(2) affinity exhibit an increased sensitivity to inhibition by phorbol myristate acetate (PMA). The effect of PMA can be prevented by pretreatment with calphostin-C. Activation of PKC by carbachol in Xenopus oocytes co-expressing M1 muscarinic receptors also causes inhibition of the channels. Calphostin-C prevents carbachol-induced inhibition, suggesting that activation of PKC is necessary for inhibition of the channels. PMA reduces open probability of the channel in cell-attached patch clamp recordings. After inhibition by PMA in cell-attached recordings, application of PIP(2) to the cytoplasmic face of excised inside-out membranes restores channel activity. PMA reduces PIP(2) content in oocyte membrane and calphostin-C prevents the reduction. These results suggest that reduction of membrane PIP(2) content contributes to the inhibition of ROMK1 channels by PKC. This mechanism may underscore the inhibition of K(+) secretion in CCD by hormones that activate PKC.
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PMID:Protein kinase C inhibits ROMK1 channel activity via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. 1261 24

Carrier-mediated urea transport allows rapid urea movement across the cell membrane, which is particularly important in the process of urinary concentration and for rapid urea equilibrium in non-renal tissues. Urea transporters mediate passive urea uptake that is inhibited by phloretin and urea analogues. Facilitated urea transporters are divided into two classes: (1) the renal tubular/testicular type of urea transporter, UT-A1 to -A5, encoded by alternative splicing of the SLC14A2 gene, and (2) the erythrocyte urea transporter UT-B1 encoded by the SLC14A1 gene. The primary structure of urea transporters is unique, consisting of two extended, hydrophobic, membrane-spanning domains and an extracellular glycosylated-connecting loop. UT-A1 is the result of a gene duplication of this two-halves-structure, and the duplicated portions are linked together by a large intracellular hydrophilic loop, carrying several putative protein kinase A (PKA) and -C (PKC) phosphorylation sites. UT-A1 is located in the apical membrane of the kidney inner medullary collecting duct cells, where it is stimulated acutely by cAMP-mediated phosphorylation in response to the antidiuretic hormone vasopressin. Vasopressin also up-regulates UT-A2 mRNA/protein expression in the descending thin limb of the loops of Henle. UT-A1 and UT-A2 are regulated independently and respond differently to changes in dietary protein content. UT-A3 and UT-A4 are located in the rat kidney medulla and UT-A5 in the mouse testis. The widely expressed UT-B participates in urea recycling in the descending vasa recta, as demonstrated by a relatively mild "urea-selective" urinary concentrating defect in transgenic UT-B null mice and individuals with the Jk(null) blood group.
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PMID:The SLC14 gene family of urea transporters. 1285 82

Exocytic insertion of H(+)-ATPase into the apical membrane of inner medullary collecting duct (IMCD) cells is dependent on a soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein target receptor (SNARE) complex. In this study we determined the role of Munc-18 in regulation of IMCD cell exocytosis of H(+)-ATPase. We compared the effect of acute cell acidification (the stimulus for IMCD exocytosis) on the interaction of syntaxin 1A with Munc-18-2 and the 31-kDa subunit of H(+)-ATPase. Immunoprecipitation revealed that cell acidification decreased green fluorescent protein (GFP)-syntaxin 1A and Munc-18-2 interaction by 49 +/- 7% and increased the interaction between GFP-syntaxin 1A and H(+)-ATPase by 170 +/- 23%. Apical membrane Munc-18-2 decreased by 27.5 +/- 4.6% and H(+)-ATPase increased by 246 +/- 22%, whereas GP-135, an apical membrane marker, did not increase. Pretreatment of IMCD cells with a PKC inhibitor (GO-6983) diminished the previously described changes in Munc-18-2-syntaxin 1A interaction and redistribution of H(+)-ATPase. In a pull-down assay of H(+)-ATPase by glutathione S-transferase (GST)-syntaxin 1A bound to beads, preincubation of beads with an approximately twofold excess of His-Munc-18-2 decreased H(+)-ATPase pulled down by 64 +/- 16%. IMCD cells that overexpress Munc-18-2 had a reduced rate of proton transport compared with control cells. We conclude that Munc-18-2 must dissociate from the syntaxin 1A protein for the exocytosis of H(+)-ATPase to occur. This dissociation leads to a conformational change in syntaxin 1A, allowing it to interact with H(+)-ATPase, synaptosome-associated protein (SNAP)-23, and vesicle-associated membrane protein (VAMP), forming the SNARE complex that leads to the docking and fusion of H(+)-ATPase vesicles.
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PMID:Munc-18-2 regulates exocytosis of H(+)-ATPase in rat inner medullary collecting duct cells. 1524 Mar 46

In the renal collecting duct (CD), water reabsorption depends on the presence of aquaporin-2 (AQP2) in the apical membrane of principal cells. AQP2 expression and subcellular repartition are under the control of AVP. Some pieces of experimental evidence indicate that additional hormonal factors, including insulin, may also control AQP2 expression and thereby CD water permeability. We have previously shown that AVP induces endogenous AQP2 expression in cultured mouse mpkCCD(cl4) CD principal cells (23). In the present study, we investigated the effect of insulin on AQP2 expression in mpkCCD(cl4) cells. Addition of insulin to the basal medium of cells grown on filters slightly increased AQP2 mRNA and protein expression, whereas insulin potentiated the effect of AVP. The potentiation of AVP-induced AQP2 expression by insulin was abolished by actinomycin D, a transcriptional inhibitor. Analysis of AQP2 protein expression under conditions of AVP washout and/or in the presence of chloroquine, a lysosomal degradation inhibitor, revealed that insulin did not significantly alter AQP2 protein degradation. Inhibition of ERK, p38 kinase, and phosphatidylinositol 3'-kinase (PI 3-kinase) activities prevented the insulin-induced stimulation of AQP2 expression, whereas inhibition of PKC has no effect. Taken together, our results indicate that insulin increased AQP2 protein expression mostly through increased AQP2 mRNA levels in cultured mpkCCD(cl4) cells. This effect most likely relies on increased AQP2 gene transcription in response to MAPK and PI 3-kinase activation.
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PMID:Insulin potentiates AVP-induced AQP2 expression in cultured renal collecting duct principal cells. 1549 47

Receptor-mediated inhibition of amiloride-sensitive sodium absorption was observed in primary and immortalized murine renal collecting duct cell (mCT12) monolayers. The addition of epidermal growth factor (EGF) to the basolateral bathing solution of polarized monolayers reduced amiloride-sensitive short-circuit current (I(sc)) by 15-25%, whereas the addition of ATP to the apical bathing solution decreased I(sc) by 40-60%. Direct activation of PKC with phorbol 12-myristate 13-acetate (PMA) and mobilization of intracellular calcium with 2,5-di-tert-butyl-hydroquinone (DBHQ) reduced amiloride-sensitive I(sc) in mCT12 monolayers by 46 +/- 4% (n = 8) and 22 +/- 2% (n = 8), respectively. Exposure of mCT12 cells to EGF, ATP, PMA, and DBHQ caused an increase in phosphorylation of p42/p44 (extracellular signal-regulated kinase; ERK1/2). Pretreatment of mCT12 monolayers with an ERK kinase inhibitor (PD-98059; 30 microM) prevented phosphorylation of p42/p44 and significantly reduced EGF, ATP, and PMA-induced inhibition of amiloride-sensitive I(sc). In contrast, pretreatment of monolayers with a PKC inhibitor (bisindolylmaleimide I; GF109203x; 1 microM) almost completely blocked the PMA-induced decrease in I(sc), but did not alter the EGF- or ATP-induced inhibition of I(sc). The DBHQ-mediated decrease in I(sc) was due to inhibition of basolateral Na(+)-K(+)-ATPase, but EGF-, ATP-, and PMA-induced inhibition was most likely due to reduced apical sodium entry (epithelial Na(+) channel activity). The results of these studies demonstrate that acute inhibition of amiloride-sensitive sodium transport by extracelluar ATP and EGF involves ERK1/2 activation and suggests a role for MAP kinase signaling as a negative regulator of electrogenic sodium absorption in epithelia.
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PMID:A role for ERK1/2 in EGF- and ATP-dependent regulation of amiloride-sensitive sodium absorption. 1563 42

The conventional protein kinase C isoenzyme beta (PKC-beta) is expressed in various structures of mouse kidney. To get insights into the function, PKC-beta knockout (-/-) and wild-type (+/+) mice were studied. Under basal conditions, PKC-beta-/- mice exhibited a higher systolic blood pressure (in awake mice), normal plasma concentrations of Na+ and K+, and normal plasma pH. Urine osmolality and 24-hour excretion of fluid, Na+, K+ and albumin were not different between genotypes, but urine pH was more alkaline in PKC-beta-/- mice. Inulin clearance experiments under anesthesia confirmed a higher systolic blood pressure and revealed normal glomerular filtration rate and fractional excretion of fluid, Na+ and K+ in PKC-beta-/- mice. The ability to restrict renal Na+ excretion in response to a low Na+ diet was unaltered in PKC-beta-/- mice. Chronic acid loading (NH4Cl) did not affect blood pH in PKC-beta+/+ mice, but induced a modest metabolic acidosis in PKC-beta-/- mice. In conclusion, first evidence is presented that (i) PKC-beta contributes to the regulation of arterial blood pressure, and (ii) PKC-beta is required for normal acid-base balance, which may relate to its expression and function in intercalated cells of the collecting duct.
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PMID:Mice lacking protein kinase C beta present modest increases in systolic blood pressure and NH4Cl-induced metabolic acidosis. 1658 76

Recent studies of the distribution of PKC isoenzymes in the mouse kidney demonstrated that PKC-alpha, -beta(I), and -delta are expressed in intercalated cells. The purpose of this study was to identify the intercalated cell subtypes that express the different PKC isoenzymes and determine the location of the PKC isoenzymes within these cells. Adult C57BL/6 mice kidney tissues were processed for multiple-labeling immunohistochemistry. Antibodies against the vacuolar H(+)-ATPase and pendrin were used to identify intercalated cell subtypes, whereas antibodies against calbindin D(28K) and aquaporin-2 (AQP2) were used to identify connecting tubule cells and principal cells of the collecting duct, respectively. Within type A intercalated cells, PKC-delta was highly expressed in the apical part of the cells, whereas immunoreactivity for both PKC-alpha and PKC-beta(I) was weak. Type B intercalated cells exhibited strong expression of PKC-alpha, -beta(I), and -delta. PKC-alpha and -beta(I) were localized throughout the cytoplasm, whereas PKC-delta was restricted to the basal domain. Within non-A-non-B cells, immunoreactivity for both PKC-alpha and PKC-beta(I) was high in intensity and localized diffusely in the cytoplasm, whereas PKC-delta was localized in the apical part of the cells. None of the PKC isoenzymes (PKC-alpha, -beta(I), or -delta) were expressed in the calbindin D(28K)-positive connecting tubule cells. Within AQP2-positive principal cells of the collecting duct, PKC-alpha was expressed on the basolateral plasma membrane, but no significant staining was detected for PKC-beta(I) and -delta. In summary, this study demonstrates distinct and differential expression patterns of PKC-alpha, -beta(I), and -delta in the three subtypes of intercalated cells in the mouse kidney.
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PMID:Expression of protein kinase C isoenzymes alpha, betaI, and delta in subtypes of intercalated cells of mouse kidney. 1673 62

In the study, the role of PKC and Ca++ in vasopressin regulation of the plasma membrane water permeability was studied in the cells of the mouse kidney collecting duct. Coefficient of osmotic water permeability of total cell surface (Pf) was calculated from the initial rate of cell swelling following the osmotic shock caused by changing the medium osmolarity from isotonic to hypotonic (300 mOsm to 200 mOsm). Desmopressin (dDAVP 1 nM) increased the Pf in hydrated mice from 168.4 +/- 11.8 microm/s up to 231.3 +/- 14.7 microm/s. The Ca++ chelator BAPTA prevented the desmopressin-induced increase in water permeability. Inhibition of PKC (Ro-31-8220 0.1 microM) also abolished the desmopressin-stimulated increase of plasma membrane water permeability, whereas inhibitor of PKC alone did not suppress the stimulation of the water permeability by db-cAMP. The PKC activity and calciumdependent second messengers seem to be important for regulation of water permeability by vasopressin.
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PMID:[Calciumdependent mechanisms in vasopressin regulation of osmotic water permeability in the mouse kidney collecting duct cells]. 1686 92

Vasopressin and angiotensin II (ANG II) play a major role in renal water and Na(+) reabsorption. We previously demonstrated that ANG II AT(1) receptor blockade decreases dDAVP-induced water reabsorption and AQP2 levels in rats, suggesting cross talk between these two peptide hormones (Am J Physiol Renal Physiol 288: F673-F684, 2005). To directly address this issue, primary cultured inner medullary collecting duct (IMCD) cells from male Sprague-Dawley rats were treated for 15 min with 1) vehicle, 2) ANG II, 3) ANG II + the AT(1) receptor blocker candesartan, 4) dDAVP, 5) ANG II + dDAVP, or 6) ANG II + dDAVP + candesartan. Immunofluorescence microscopy revealed that 10(-8) M ANG II or 10(-11) M dDAVP (protocol 1) was associated with increased AQP2 labeling of the plasma membrane and decreased cytoplasmic labeling, respectively. cAMP levels increased significantly in response to 10(-8) M ANG II and were potentiated by cotreatment with 10(-11) M dDAVP. Consistent with this finding, immunoblotting revealed that this cotreatment significantly increased expression of phosphorylated AQP2. ANG II-induced AQP2 targeting was blocked by 10(-5) M candesartan. In protocol 2, treatment with a lower concentration of dDAVP (10(-12) M) or ANG II (10(-9) M) did not change subcellular AQP2 distribution, whereas 10(-12) M dDAVP + 10(-9) M ANG II enhanced AQP2 targeting. This effect was inhibited by cotreatment with 10(-5) M candesartan. ANG II-induced cAMP accumulation and AQP2 targeting were inhibited by inhibition of PKC activity. In conclusion, ANG II plays a role in the regulation of AQP2 targeting to the plasma membrane in IMCD cells through AT(1) receptor activation and potentiates the effect of dDAVP on AQP2 plasma membrane targeting.
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PMID:Increased AQP2 targeting in primary cultured IMCD cells in response to angiotensin II through AT1 receptor. 1689 88

Cilia are specialized organelles that play an important role in several biological processes, including mechanosensation, photoperception, and osmosignaling. Mutations in proteins localized to cilia have been implicated in a growing number of human diseases. In this study, we demonstrate that the von Hippel-Lindau (VHL) protein (pVHL) is a ciliary protein that controls ciliogenesis in kidney cells. Knockdown of pVHL impeded the formation of cilia in mouse inner medullary collecting duct 3 kidney cells, whereas the expression of pVHL in VHL-negative renal cancer cells rescued the ciliogenesis defect. Using green fluorescent protein-tagged end-binding protein 1 to label microtubule plus ends, we found that pVHL does not affect the microtubule growth rate but is needed to orient the growth of microtubules toward the cell periphery, a prerequisite for the formation of cilia. Furthermore, pVHL interacts with the Par3-Par6-atypical PKC complex, suggesting a mechanism for linking polarity pathways to microtubule capture and ciliogenesis.
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PMID:The von Hippel-Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. 1710 96


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