Role of CFTR and ClC-5 in modulating vacuolar H+-ATPase activity in kidney proximal tubule.
ABSTRACT 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.
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Chapter: Dent Disease[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.
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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.2011.220Kidney International 11/2011; 80(9):907-9. DOI:10.1038/ki.2011.220 · 8.52 Impact Factor
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ABSTRACT: Insects contain an array of hormones that coordinate the actions of the excretory system to achieve osmotic and ionic balance. In the hematophagous insect, Rhodnius prolixus, two diuretic hormones have been identified, serotonin (5HT) and a corticotropin releasing factor-related peptide (RhoprDH), and both lead to an increase in fluid secretion by Malpighian tubules (MTs). However, only 5HT activates reabsorption by the lower MTs to recover K(+) and Cl(-). An anti-diuretic hormone (RhoprCAPA-α2) is believed to coordinate the cessation of the rapid diuresis following blood meal engorgement. However, the role of RhoprCAPA-α2 on fluid secretion by MTs stimulated by RhoprDH was previously unknown. Here we demonstrate that, unlike the inhibitory effect on 5HT-stimulated secretion by MTs, RhoprCAPA-α2 does not inhibit secretion stimulated by RhoprDH although it does abolish the synergism that occurs between the two diuretic hormones. In addition, we show that the natriuresis elicited by either diuretic hormone is reduced by RhoprCAPA-α2. Using electrophysiological tools, we investigate the possible mechanism by which this complex regulatory pathway is achieved. Analysis of the pH of secreted fluid as well as the triphasic response in transepithelial potential in MTs treated with diuretic hormones, suggests that RhoprCAPA-α2 does not inhibit the V-type H(+) ATPase. Taken together, these results indicate that RhoprCAPA-α2 functions to reduce the rapid diuresis following blood feeding, and in addition, it inhibits the natriuresis associated with diuretic hormone stimulated MTs. This may reflect an important regulatory mechanism related to the slow diuresis that occurs as the K(+)-rich blood cells are digested.Journal of insect physiology 12/2011; 58(4):534-42. DOI:10.1016/j.jinsphys.2011.11.020 · 2.50 Impact Factor