Track topics on Twitter Track topics that are important to you
Excessive red cell dehydration contributes to the pathophysiology of sickle cell disease (SCD). The densest fraction of sickle red cells (with the highest corpuscular hemoglobin concentration) undergoes the most rapid polymerization of deoxy-hemoglobin S, leading to accelerated cell sickling and increased susceptibility to endothelial activation, red cell adhesion, and vaso-occlusion. Increasing red cell volume in order to decrease red cell density can thus serve as an adjunct therapeutic goal in SCD. Regulation of circulating mouse red cell volume and density is mediated largely by the Gardos channel, KCNN4, and the K-Cl cotransporters, KCC3 and KCC1. Whereas inhibition of the Gardos channel in subjects with sickle cell disease increased red cell volume, decreased red cell density, and improved other hematological indices in subjects with SCD, specific KCC inhibitors have not been available for testing. We therefore investigated the effect of genetic inactivation of KCC3 and KCC1 in the SAD mouse model of sickle red cell dehydration, finding decreased red cell density and improved hematological indices. We describe here generation of mice genetically deficient in the three major red cell volume regulatory gene products, KCNN4, KCC3, and KCC1 in C57BL6 non-sickle and SAD sickle backgrounds. We show that combined loss-of-function of all three gene products in SAD mice leads to incrementally increased MCV, decreased CHCM and % hyperchromic cells, decreased red cell density (phthalate method), increased resistance to hypo-osmotic lysis, and increased cell K content. The data show that combined genetic deletion of the Gardos channel and K-Cl cotransporters in a mouse SCD model decreases red cell density and improves several hematological parameters, supporting the strategy of combined pharmacological inhibition of these ion transport pathways in the adjunct treatment of human SCD.
This article was published in the following journal.
Name: Blood cells, molecules & diseases
Corrigendum to "Combined genetic disruption of K-Cl cotransporters and Gardos channel KCNN4 rescues erythrocyte dehydration in the SAD mouse model of sickle cell disease" Blood Cells Mol. Dis. (2019) start page-end page not yet assigned https://doi.org/10.1016/j.bcmd.2019.102346.
β-thalassemia (β-Thal) is caused by defective β-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulati...
Basolateral membrane K channels play a key role in basal and agonist stimulated Cl transport across airway epithelial cells by generating a favourable electrical driving force for Cl efflux. The K cha...
Neoadjuvant PD-1 Blockade in Resectable Lung Cancer; Nivolumab and Ipilimumab in Advanced Melanoma; Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma; Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy; Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma; Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma; Niv
The effect of HS on changes in erythrocyte volume was studied by spectrophotometrical and potentiometric methods. It was found that HS donor NaHS (2.5, 10, and 100 μM) induced an increase in erythroc...
The purpose of this study is to compare the dual channel intravenous patient-controlled analgesia (IV-PCA) with single channel elastomeric pump (only one channel of dual channel pump is us...
This prospective randomized controlled trial compared integrated water jet channel colonoscopy with traditional accessory channel colonoscopy in cecal insertion time among patients undergo...
The purpose of this study is to investigate which combination therapy is more effective for improving the blood pressure (BP) and reducing target organ damage in Japanese hypertensive pati...
This clinical RCT study intends to combined different forms of multi-channel tDCS with the routine cognitive training process to treat patients with post-stroke cognitive dysfunction. The...
20 users of Ness L300, FES device for ankle dorsiflexion will wear the same FES cuff, yet instead of a single channel stimulation, they will be stimulated with two channels. the purpose of...
Production of new arrangements of DNA by various mechanisms such as assortment and segregation, CROSSING OVER; GENE CONVERSION; GENETIC TRANSFORMATION; GENETIC CONJUGATION; GENETIC TRANSDUCTION; or mixed infection of viruses.
Group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. It is inherited as an X-linked or autosomal recessive defect. Mutations occurring in many different genes cause human Severe Combined Immunodeficiency (SCID).
A voltage-gated sodium channel subtype that mediates the sodium ion PERMEABILITY of CARDIOMYOCYTES. Defects in the SCN5A gene, which codes for the alpha subunit of this sodium channel, are associated with a variety of CARDIAC DISEASES that result from loss of sodium channel function.
The discipline studying genetic composition of populations and effects of factors such as GENETIC SELECTION, population size, MUTATION, migration, and GENETIC DRIFT on the frequencies of various GENOTYPES and PHENOTYPES using a variety of GENETIC TECHNIQUES.
Voltage-gated sodium channel subunits that play a role in the assembly, expression, and functional modulation of the sodium channel. They form a heterotrimeric complex with the pore-forming sodium channel alpha subunits.
Blood is a specialized bodily fluid that delivers necessary substances to the body's cells (in animals) – such as nutrients and oxygen – and transports waste products away from those same cells. In vertebrates, it is composed of blo...