It has been widely accepted that chloride ions moving along chloride channels act to dissipate the electrical gradient established by the electrogenic transport of H(+) ions performed by H(+)-ATPase into subcellular vesicles. Largely known in intracellular compartments, this mechanism is also important at the plasma membrane of cells from various tissues, including kidney. The present work was performed to study the modulation of plasma membrane H(+)-ATPase by chloride channels, in particular, CFTR and ClC-5 in kidney proximal tubule.
Using in vivo stationary microperfusion, it was observed that ATPase-mediated HCO(3)(-) reabsorption was significantly reduced in the presence of the Cl(-) channels inhibitor NPPB. This effect was confirmed in vitro by measuring the cell pH recovery rates after a NH(4)Cl pulse in immortalized rat renal proximal tubule cells, IRPTC. In these cells, even after abolishing the membrane potential with valinomycin, ATPase activity was seen to be still dependent on Cl(-). siRNA-mediated CFTR channels and ClC-5 chloride-proton exchanger knockdown significantly reduced H(+)-ATPase activity and V-ATPase B2 subunit expression.
These results indicate a role of chloride in modulating plasma membrane H(+)-ATPase activity in proximal tubule and suggest that both CFTR and ClC-5 modulate ATPase activity.
"Carcinoma renal murine (Renca)  and immortalized rat proximal tubule cells (IRPTC)  were kindly provided by Dr. Maria Helena Bellini (Institute of Energy and Nuclear Research, IPEN, São Paulo, Brazil) and Dr. Maria Oliveira de Souza (Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil), respectively. Human umbilical vein endothelial cells (HUVEC -CRL 1730) were obtained from the American Type Culture Collection (Mannasa, VA, USA). "
[Show abstract][Hide abstract] ABSTRACT: Background
Renal cell carcinoma (RCC) is the most common type of kidney cancer, and represents the third most common urological malignancy. Despite the advent of targeted therapies for RCC and the improvement of the lifespan of patients, its cost-effectiveness restricted the therapeutic efficacy. In a recent report, we showed that synthetic phosphoethanolamine (Pho-s) has a broad antitumor activity on a variety of tumor cells and showed potent inhibitor effects on tumor progress in vivo.
We show that murine renal carcinoma (Renca) is more sensitive to Pho-s when compared to normal immortalized rat proximal tubule cells (IRPTC) and human umbilical vein endothelial cells (HUVEC). In vitro anti-angiogenic activity assays show that Pho-s inhibits endothelial cell proliferation, migration and tube formation. In addition, Pho-s has anti-proliferative effects on HUVEC by inducing a cell cycle arrest at the G2/M phase. It causes a decrease in cyclin D1 mRNA, VEGFR1 gene transcription and VEGFR1 receptor expression. Pho-s also induces nuclear fragmentation and affects the organization of the cytoskeleton through the disruption of actin filaments. Additionally, Pho-s induces apoptosis through the mitochondrial pathway. The putative therapeutic potential of Pho-s was validated in a renal carcinoma model, on which our remarkable in vivo results show that Pho-s potentially inhibits lung metastasis in nude mice, with a superior efficacy when compared to Sunitinib.
Taken together, our findings provide evidence that Pho-s is a compound that potently inhibits lung metastasis, suggesting that it is a promising novel candidate drug for future developments.
PLoS ONE 03/2013; 8(3):e57937. DOI:10.1371/journal.pone.0057937 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and chronic kidney disease (CKD). Males younger than age ten years may manifest only low molecular weight (LMW) proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. Rickets or osteomalacia are occasionally observed, and mild short stature, although underappreciated, may be a common occurrence. Disease severity can vary within the same family. Males with Dent disease 2 (caused by mutations in OCRL) are at increased risk for intellectual disability. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely if ever develop CKD.
The diagnosis is based on renal findings and/or a family history consistent with X-linked inheritance. A mutation in CLCN5 accounts for approximately 60% of those with Dent disease (known as Dent disease 1); a mutation in OCRL accounts for approximately 15% of those with Dent disease (known as Dent disease 2). Molecular genetic testing for both genes is clinically available.
Treatment of manifestations: The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD). No randomized controlled trials have been performed. Although thiazide diuretics can decrease urinary calcium excretion in boys with Dent disease, side effects limit their use. The effectiveness of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) in children with proteinuria to prevent or delay further loss of kidney function is unclear. Renal replacement therapy is necessary in those with ESRD. Prevention of secondary complications: Bone disease, when present, responds to vitamin D supplementation and phosphorus repletion. Growth failure may be treated with human growth hormone without adversely affecting kidney function. Surveillance: Monitor at least annually urinary calcium excretion, renal function (glomerular filtration rate [GFR]), and the parameters used to stage CKD (i.e., blood pressure, hematocrit/hemoglobin, and serum calcium and phosphorous concentrations). Monitor more frequently when CKD is evident. Agents/circumstances to avoid: Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents). Evaluation of relatives at risk: Clarify the genetic status of at-risk male relatives by either molecular genetic testing if the mutation in the family is known or measurement of urinary excretion of low molecular weight proteins (LMWPs).
Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be a carrier of the mutation. If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%: males who inherit the mutation will be affected; females who inherit the mutation will be carriers and will usually not be significantly affected. Affected males pass the disease-causing mutation to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation in the family has been identified.
GeneReviews™, Edited by Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam; University of Washington, Seattle.
[Show abstract][Hide abstract] ABSTRACT: Xu et al. identify Slc26a11, a novel member of the Slc26 anion exchanger family, as an electrogenic (Cl-)(n)/HCO3- exchanger. Functional characterization of this transporter suggests that Slc26a11 mediates classical electroneutral Cl-/HCO3- exchange but also exhibits an electrogenic Cl- conductance. In the kidney, Slc26a11 colocalizes with the vacuolar H+-ATPase in intercalated cells, emphasizing the cooperation of the proton pump with chloride transporters. Kidney International (2011) 80, 907 -909; doi:10.1038/ki.2011.220
Kidney International 11/2011; 80(9):907-9. DOI:10.1038/ki.2011.220 · 8.56 Impact Factor
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