Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice

Rust, Marco B.; Alper, Seth L.; Rudhard, York; Shmukler, Boris E.; Vicente, Rubén; Brugnara, Carlo; Trudel, Marie; Jentsch, Thomas J.; Hübner, Christian A.

doi:10.1172/jci30630

Cited by 79 publications

(92 citation statements)

References 43 publications

(53 reference statements)

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“…(b) Blockade of KCC activity in wild-type and KCC3-overexpressed tumor cells is accompanied by the increased abundances of E-cadherin and h-catenin in cell-cell junctions. The cellular KCC activity is mediated largely from KCC3 (3,6,31). Therefore, we suggest that there is a tight link between the expression and activity of KCC3 and EMT in cervical cancer cells.…”

Section: Discussionmentioning

confidence: 80%

“…The neuron-specific KCC2 is critical for the maturation of inhibitory g-aminobutyric acid responses in the central nervous system by the control of intracellular Cl À concentration (4,5). KCC activity in RBC was undiminished in KCC1 knockout mice, decreased in KCC3 knockout mice, and almost completely abolished in mice lacking both isoforms, indicating that KCC activity of mouse RBC is mediated largely by KCC3 (6). Loss of KCC3 caused deafness, neurodegeneration, and reduced seizure threshold (7).…”

Section: Introductionmentioning

confidence: 99%

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KCl Cotransporter-3 Down-regulates E-Cadherin/β-Catenin Complex to Promote Epithelial-Mesenchymal Transition

et al. 2007

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The potassium chloride cotransporter (KCC) is a major determinant of osmotic homeostasis and plays an emerging role in tumor biology. Here, we investigate if KCC is involved in the regulation of epithelial-mesenchymal transition (EMT), a critical cellular event of malignancy. E-cadherin and B-catenin colocalize in the cell-cell junctions, which becomes more obvious in a time-dependent manner by blockade of KCC activity in cervical cancer SiHa and CaSki cells. Real-time reverse transcription-PCR on the samples collected from the laser microdissection indicates that KCC3 is the most abundant KCC isoform in cervical carcinoma. The characteristics of EMT appear in KCC3-overexpressed, but not in KCC1-or KCC4-overexpressed cervical cancer cells, including the elongated cell shape, increased scattering, down-regulated epithelial markers (E-cadherin and B-catenin), and up-regulated mesenchymal marker (vimentin). Some cellular functions are enhanced by KCC3 overexpression, such as increased invasiveness and proliferation, and weakened cell-cell association. KCC3 overexpression decreases mRNA level of E-cadherin. The promoter activity assays of various regulatory sequences confirm that KCC3 expression is a potent negative regulator for human E-cadherin gene expression. The proteosome inhibitor restores the decreased protein abundance of B-catenin by KCC3 overexpression. In the surgical specimens of cervical carcinoma, the decreased E-cadherin amount was accompanied by the increased KCC3 abundance. Vimentin begins to appear at the invasive front and becomes significantly expressed in the tumor nest. In conclusion, KCC3 down-regulates E-cadherin/B-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of B-catenin protein. The disruption of E-cadherin/B-catenin complex formation promotes EMT, thereby stimulating tumor progression. [Cancer Res 2007;67(22):11064-73]

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

KCl Cotransporter-3 Down-regulates E-Cadherin/β-Catenin Complex to Promote Epithelial-Mesenchymal Transition

et al. 2007

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“…Neomycin-resistant clones were screened for homologous recombination by Southern blot analysis of a genomic EcoRI digest with an external probe exploiting a novel EcoRI restriction site introduced with the third loxP site. Neomycin-resistant clones that had undergone homologous recombination were transfected with a plasmid expressing Cre recombinase (49). Resulting clones were tested for the extent of the DNA excision.…”

Section: Micementioning

confidence: 99%

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

Heinze¹,

Seniuk²,

Sokolov³

et al. 2014

J. Clin. Invest.

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130

152

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High blood pressure is the leading risk factor for death worldwide. One of the hallmarks is a rise of peripheral vascular resistance, which largely depends on arteriole tone. Ca 2+ -activated chloride currents (CaCCs) in vascular smooth muscle cells (VSMCs) are candidates for increasing vascular contractility. We analyzed the vascular tree and identified substantial CaCCs in VSMCs of the aorta and carotid arteries. CaCCs were small or absent in VSMCs of medium-sized vessels such as mesenteric arteries and larger retinal arterioles. In small vessels of the retina, brain, and skeletal muscle, where contractile intermediate cells or pericytes gradually replace VSMCs, CaCCs were particularly large. Targeted disruption of the calcium-activated chloride channel TMEM16A, also known as ANO1, in VSMCs, intermediate cells, and pericytes eliminated CaCCs in all vessels studied. Mice lacking vascular TMEM16A had lower systemic blood pressure and a decreased hypertensive response following vasoconstrictor treatment. There was no difference in contractility of medium-sized mesenteric arteries; however, responsiveness of the aorta and small retinal arterioles to the vasoconstrictioninducing drug U46619 was reduced. TMEM16A also was required for peripheral blood vessel contractility, as the response to U46619 was attenuated in isolated perfused hind limbs from mutant mice. Out data suggest that TMEM16A plays a general role in arteriolar and capillary blood flow and is a promising target for the treatment of hypertension.

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“…MCV correlated with Na + K + ATPase activity in mammalian erythrocytes (Katyukhin et al, 1998) and erythrocytes from sheep with extra α-gene were larger (with increased MCV) and had increased EOF (Pieragostini et al, 2003). Erythrocyte volume was altered in mice lacking KCl cotransporters and osmotic sensitivity was increased (Rust et al, 2007). Reticulocytes and young erythrocytes have higher MCV than mature erythrocytes and have higher activity of K-Cl cotransporters that mediate volume reduction and affect osmotic resistance (Quarmyne et al, 2011).…”

Section: Resultsmentioning

confidence: 99%

Phenotypic drift in osmotic fragility of Sahel goat erythrocytes associated with variability of median fragility

Igbokwe¹,

Ojo²,

Igbokwe³

2015

Sokoto J. Vet. Sc.

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A typical mammalian erythrocyte fragility phenotype (EFP) exhibits a sigmoidal curve of the dependence of fragilities (% haemolysis) on hypotonic saline concentrations, but the goat EFP tends to be hyperbolic. Physiological variation in median erythrocyte fragility (MEF) and the associated EFP of Sahel goats was investigated. Erythrocyte osmotic fragility (EOF) was determined in hypotonic saline using heparinized venous blood from 47 goats (23 males and 24 non-pregnant dry females) aged 1-4 years and weighing 18.87 ± 6.32 (9-30) kg. Packed cell volume (PCV), erythrocyte count and mean corpuscular volume (MCV) were also estimated. Low, medium and high EFP were based on MEF of < 7, 7-8 and > 8 g/L, respectively. MEF of all the goats was 7.5 ± 0.6 (5.9-8.4) g/L. Phenotypic drift from sigmoidal to hyperbolic EOF curve was observed at the lower and upper limits of the phenotypic variation. Frequencies of occurrence of low, medium and high EFP were not different (p > 0.05) between males and females. Fragiligrams of low, medium and high EFP separated at erythrocyte fragilities of 10-70% and saline tonicity of 7-8 g/L. The saline concentrations causing fragilities of 10-70% differed (p < 0.05) among the phenotypes. There was no correlation (r = -0.28, -0.30; p > 0.05) between MEF and MCV or PCV, and between PCV and MCV. In conclusion, phenotypic drift in EOF occurred in Sahel goats without influence by erythrocyte parameters and represented the physiological variability of EOF endpoint estimates that would serve as reference limits in evaluation of erythrocyte membrane defects.

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Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice

Cited by 79 publications

References 43 publications

KCl Cotransporter-3 Down-regulates E-Cadherin/β-Catenin Complex to Promote Epithelial-Mesenchymal Transition

KCl Cotransporter-3 Down-regulates E-Cadherin/β-Catenin Complex to Promote Epithelial-Mesenchymal Transition

Disruption of vascular Ca2+-activated chloride currents lowers blood pressure

Phenotypic drift in osmotic fragility of Sahel goat erythrocytes associated with variability of median fragility

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