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Paul JM Savelkoul Fabrizio De Mattia Yuedan Li Erik‐Jan Kamsteeg Irene BM Konings Peter van der Sluijs Peter MT Deen 《Human mutation》2009,30(10):E891-E903
Vasopressin regulates human water homeostasis by re‐distributing homotetrameric aquaporin‐2 (AQP2) water channels from intracellular vesicles to the apical membrane of renal principal cells, a process in which phosphorylation of AQP2 at S256 by cAMP‐dependent protein kinase A (PKA) is thought to be essential. Dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by AQP2 gene mutations. Here, we investigated a reported patient case of dominant NDI caused by a novel p.R254Q mutation. Expressed in oocytes, AQP2‐p.R254Q appeared to be a functional water channel, but was impaired in its transport to the cell surface to the same degree as AQP2‐p.S256A, which mimics non‐phosphorylated AQP2. In polarized MDCK cells, AQP2‐p.R254Q was retained and was distributed similarly to that of unstimulated wt‐AQP2 or AQP2‐p.S256A. Upon co‐expression, AQP2‐p.R254Q interacted with, and retained wt‐AQP2 in intracellular vesicles. In contrast to wild‐type AQP2, forskolin did not increase AQP2‐p.R254Q phosphorylation at S256 or its translocation to the apical membrane. Mimicking constitutive phosphorylation in AQP2‐p.R254Q with the p.S256D mutation, however, rescued its apical membrane expression. These date indicate that a lack of S256 phosphorylation is the sole cause of dominant NDI here, and thereby, p.R254Q is a loss of function instead of a gain of function mutation in dominant NDI. © 2009 Wiley‐Liss, Inc. 相似文献
73.
M Duarte-Araújo C Nascimento MA Timóteo MT Magalh?es-Cardoso P Correia-de-Sá 《British journal of pharmacology》2009,156(3):519-533
Background and purpose:
The relative contribution of distinct ecto-nucleotidases to the modulation of purinergic signalling may depend on differential tissue distribution and substrate preference.Experimental approach:
Extracellular ATP catabolism (assessed by high-performance liquid chromatography) and its influence on [3H]acetylcholine ([3H]ACh) release were investigated in the myenteric plexus of rat ileum in vitro.Key results:
ATP was primarily metabolized via ecto-ATPDase (adenosine 5′-triphosphate diphosphohydrolase) into AMP, which was then dephosphorylated into adenosine by ecto-5′-nucleotidase. Alternative conversion of ATP into ADP by ecto-ATPase (adenosine 5′-triphosphatase) was more relevant at high ATP concentrations. ATP transiently increased basal [3H]ACh outflow in a 2′,3′-O-(2,4,6-trinitrophenyl)adenosine-5′-triphosphate (TNP-ATP)-dependent, tetrodotoxin-independent manner. ATP and ATPγS (adenosine 5′-[γ-thio]triphosphate), but not α,β-methyleneATP, decreased [3H]ACh release induced by electrical stimulation. ADP and ADPβS (adenosine 5′[β-thio]diphosphate) only decreased evoked [3H]ACh release. Inhibition by ADPβS was prevented by MRS 2179 (2′-deoxy-N6-methyl adenosine 3′,5′-diphosphate diammonium salt, a selective P2Y1 antagonist); blockade of ADP inhibition required co-application of MRS 2179 plus adenosine deaminase (which inactivates endogenous adenosine). Blockade of adenosine A1 receptors with 1,3-dipropyl-8-cyclopentyl xanthine enhanced ADPβS inhibition, indicating that P2Y1 stimulation is cut short by tonic adenosine A1 receptor activation. MRS 2179 facilitated evoked [3H]ACh release, an effect reversed by the ecto-ATPase inhibitor, , which delayed ATP conversion into ADP without affecting adenosine levels. ARL67156Conclusions and implications:
ATP transiently facilitated [3H]ACh release from non-stimulated nerve terminals via prejunctional P2X (probably P2X2) receptors. Hydrolysis of ATP directly into AMP by ecto-ATPDase and subsequent formation of adenosine by ecto-5′-nucleotidase reduced [3H]ACh release via inhibitory adenosine A1 receptors. Stimulation of inhibitory P2Y1 receptors by ADP generated alternatively via ecto-ATPase might be relevant in restraining ACh exocytosis when ATP saturates ecto-ATPDase activity. 相似文献74.
75.
S Caserío C Gallego P Martin MT Moral CR Pallás A Galindo 《Acta paediatrica (Oslo, Norway : 1992)》2010,99(10):1571-1577
Aim: To analyse the main prenatal and postnatal features of congenital chylothorax (CC), and the outcome including mid‐term follow‐up. Methods: We searched our databases for CC diagnosed between 1990 and 2006. Data of 29 cases were retrieved and analysed. Follow‐up until 3 years of age was available for all patients. Results: Most patients were diagnosed prenatally (94%) and most cases were complicated by foetal hydrops (66.7%). The overall survival rate at 3 years was 56%. A significantly poorer outcome was observed when foetal hydrops, preterm birth < 34 weeks, large effusions and/or early‐onset pneumothorax were present. An important but not significant improvement in the survival rate was observed through the study period; while in 1990–1998, the survival rate was 41.7%, from 1999 to 2006 it was 66.7% (p = 0.19). In the mid‐term follow‐up, we did not observe any recurrence of CC and most infants remain asymptomatic. However, 27% of survivors were diagnosed as having asthma in early infancy. Conclusion: CC still carries a significant risk of perinatal mortality. However, continuous advances in foetal and neonatal medicine are improving the prognosis of these patients, and nowadays most of them are likely to survive. Beyond the neonatal period, most survivors have an uneventful outcome. 相似文献
76.
Oxidative stress can generate a mass of oxygen free radicals (OFR) in the cells, and these OFRs can induce several acute and chronic symptoms and diseases. If the amount of the generated OFRs overwhelms the antioxidant capacity of the cells, the pathophysiological changes may lead to the death of the cell or the development of chronic degenerative diseases. 相似文献
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MG Pacheco-Tovar E Avalos-Díaz E Vega-Memije JJ Bollain-y-Goytia E López-Robles MT Hojyo-Tomoka L Domínguez-Soto R Herrera-Esparza 《Journal of the European Academy of Dermatology and Venereology》2009,23(6):697-701
Background Pemphigus is an autoimmune disease characterized by the formation of intra-epidermal blisters. Patients develop auto-antibodies against desmoglein 1 and 3 proteins and induce acantholysis.
Objective This work addresses the issue of whether the Fas pathway mediates acantholysis. Furthermore, the possible suppliers of the Fas pathway were investigated.
Methods Seventeen biopsies of pemphigus patients were studied by haematoxylin and eosin staining, and apoptosis was defined by TUNEL. The expression of Fas, FasL and caspase 3 was studied by in situ hybridization and immunohistochemistry. Cell infiltrates were studied by immunofluorescence with monoclonal anti-CD3, CD4, CD8, CD19 and CD69.
Results All of the biopsies showed intra-epidermal blisters, acantholytic cells and inflammatory infiltrates. The blisters expressed Fas, FasL and caspase 3. Cell infiltrates were composed of CD8 and a few CD4+ CD69+ cells. Additionally, CD19+ cells were detected. Interestingly, the Fas expression was increased in acantholytic cells and perilesional keratinocytes. Incidentally, these cells exhibited apoptotic features. Interestingly, the CD8 cells expressed FasL.
Conclusion This paper presents the morphological evidence that apoptosis and acantholysis are linked. Therefore, the Fas pathway is associated with CD8 cells in pemphigus lesions.
None declared. 相似文献
Objective This work addresses the issue of whether the Fas pathway mediates acantholysis. Furthermore, the possible suppliers of the Fas pathway were investigated.
Methods Seventeen biopsies of pemphigus patients were studied by haematoxylin and eosin staining, and apoptosis was defined by TUNEL. The expression of Fas, FasL and caspase 3 was studied by in situ hybridization and immunohistochemistry. Cell infiltrates were studied by immunofluorescence with monoclonal anti-CD3, CD4, CD8, CD19 and CD69.
Results All of the biopsies showed intra-epidermal blisters, acantholytic cells and inflammatory infiltrates. The blisters expressed Fas, FasL and caspase 3. Cell infiltrates were composed of CD8 and a few CD4
Conclusion This paper presents the morphological evidence that apoptosis and acantholysis are linked. Therefore, the Fas pathway is associated with CD8 cells in pemphigus lesions.
Conflicts of interest
None declared. 相似文献
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