scholarly journals Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.

1995 ◽  
Vol 6 (2) ◽  
pp. 295-301
Author(s):  
P E DeFranco ◽  
L Haragsim ◽  
P G Schmitz ◽  
B Bastani
Keyword(s):  
Renal Biopsy ◽  
Renal Tubular Acidosis ◽  
Collecting Duct ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Hydrogen Ion ◽  
Intercalated Cells ◽  
Band 3 Protein ◽  
Ion Secretion ◽  
Renal Tubular

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Preservation of intercalated cell H(+)-ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis.

1997 ◽  
Vol 8 (7) ◽  
pp. 1109-1117
Author(s):  
B Bastani ◽  
D Underhill ◽  
N Chu ◽  
R D Nelson ◽  
L Haragsim ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Renal Tubular Acidosis ◽  
Frozen Section ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Distal Renal Tubular Acidosis ◽  
Intercalated Cells ◽  
Urine Ph ◽  
Control Serum ◽  
Renal Tubular

In patients with Sjögren's syndrome and a secretory-defect distal renal tubular acidosis (dRTA), absence of vacuolar H(+)-ATPase from collecting duct intercalated cells has been reported. The H(+)-ATPase was examined in two patients with lupus nephritis and hyperkalemic (presumed voltage defect) dRTA. Both patients had a positive urine anion gap, alkaline urine despite acidemia, no rise in urine PCO2 with alkaluria, a urine pH > 5.5, and urine potassium excretion rate not significantly increased after 80 mg of intravenous furosemide. In both patients, immunocytochemistry of renal biopsy frozen sections with an anti-H(+)-ATPase monoclonal antibody showed bright staining of the proximal tubule brush border and collecting duct intercalated cells. In one patient, routine immunofluorescence analysis of a frozen section of her kidney biopsy with antihuman IgG showed staining of the collecting duct, indicative of autoantibodies to this segment. Moreover, rat kidney sections incubated with her serum showed labeling of the intercalated cells. On immunoblots of human kidney microsomal membranes performed with serum from both patients, an immunoreactive polypeptide was observed at M(r) approximately 56 kD that was not seen with control serum. Neither patient's sera reacted with affinity-purified bovine H(+)-ATPase or with lysates from 293 cell fibroblasts in which either of both isoforms of the human H(+)-ATPase B subunit (56 kD) were expressed. These findings demonstrate that the spectrum of dRTA includes the preservation of H(+)-ATPase in intercalated cells, in patients with presumed voltage defect dRTA. Moreover, some patients may have autoantibodies to the intercalated cells that are not directed to subunits of the H(+)-ATPase.

The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene

1998 ◽  
Vol 76 (5) ◽  
pp. 723-728 ◽  
Author(s):  
Lesley J Bruce ◽  
Robert J Unwin ◽  
Oliver Wrong ◽  
Michael JA Tanner
Keyword(s):  
Renal Tubular Acidosis ◽  
Anion Exchanger ◽  
Autosomal Dominant ◽  
Collecting Duct ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Xenopus Laevis Oocytes ◽  
Red Cell ◽  
Transport Activity ◽  
Renal Tubular

In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone disease. The condition can be familial, when it is usually inherited as an autosomal dominant, though there is a rarer autosomal recessive form associated with nerve deafness. It has been shown that the autosomal dominant form of dRTA is associated with a defect in the anion exchanger (AE1) of the renal collecting duct intercalated cell. This transporter is a product of the same gene (AE1) as the erythrocyte anion exchanger, band 3. In this review we will look at the evidence for this association. Studies of genomic DNA from families with this disorder have shown, both by genetic linkage studies and by DNA sequencing, that affected individuals are heterozygous for mutations in the AE1 gene whilst unaffected family members have a normal band 3 sequence. Mutations have been found in the region of proposed helices 6 and 7 of the membrane domain of band 3 and involve amino acids Arg-589 and Ser-613, and in the COOH-terminal domain of band 3. Studies of red cell band 3 from these families have provided information on the effect these mutations have on the structure and function of erythrocyte band 3. Expression studies of the erythroid and kidney isoforms of the mutant AE1 proteins, in Xenopus laevis oocytes, have shown that they retained chloride transport activity, suggesting that the disease in the dRTA families is not related simply to the anion transport activity of the mutated proteins. A possible explanation for the dominant effect of these mutant AE1 proteins in the kidney cell is that these mutations affect the targeting of AE1 from the basolateral to the apical membrane of the alpha-intercalated cell.Key words: erythrocyte, kidney, acidosis.

Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin

2005 ◽  
Vol 288 (1) ◽  
pp. F40-F47 ◽  
Author(s):  
Seiji Watanabe ◽  
Shuichi Tsuruoka ◽  
Soundarapandian Vijayakumar ◽  
Gunter Fischer ◽  
Yixin Zhang ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Renal Tubular Acidosis ◽  
Cyclophilin A ◽  
Distal Renal Tubular Acidosis ◽  
Apical Surface ◽  
Intercalated Cells ◽  
Ppiase Activity ◽  
Fk 506 ◽  
Isomerase Activity ◽  
Renal Tubular

Cyclosporin A (CsA), a widely used immunosuppressant, causes distal renal tubular acidosis (dRTA). It exerts its immunosuppressive effect by a calcineurin-inhibitory complex with its cytosolic receptor, cyclophilin A. However, CsA also inhibits the peptidyl prolyl cis-trans isomerase (PPIase) activity of cyclophilin A. We studied HCO3− transport and changes in β-intercalated cell pH on luminal Cl− removal in isolated, perfused rabbit cortical collecting tubules (CCDs) before and after exposure to media pH 6.8 for 3 h. Acid incubation causes adaptive changes in β-intercalated cells by extracellular deposition of hensin ( J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO3− secretory flux, estimated as the difference between net flux and that after Cl− removal from the lumen, was −6.7 ± 0.2 pmol·min−1·mm−1 and decreased to −1.3 ± 0.2 after acid incubation. CsA in the bath prevented the adaptive decreases in HCO3− secretion and apical Cl−:HCO3− exchange. To determine the mechanism, we incubated CCDs with FK-506, which inhibits calcineurin activity independently of the host cell cyclophilin. FK-506 did not prevent the acid-induced adaptive decrease in unidirectional HCO3− secretion. However, [AD-Ser]8 CsA, a CsA derivative, which does not inhibit calcineurin but inhibits PPIase activity of cyclophilin A, completely blocked the effect of acid incubation on apical Cl−:HCO3− exchange. Acid incubation resulted in prominent “clumpy” staining of extracellular hensin and diminished apical surface of β-intercalated cells [smaller peanut agglutinin (PNA) caps]. CsA and [AD-Ser]8 CsA prevented most hensin staining and the reduction of apical surface; PNA caps were more prominent. We suggest that hensin polymerization around adapting β-intercalated cells requires the PPIase activity of cyclophilins. Thus CsA is able to prevent this adaptation by inhibition of a peptidyl prolyl cis-trans isomerase activity. Such inhibition may cause dRTA during acid loading.

scholarly journals Acidosis and Deafness in Patients with Recessive Mutations in FOXI1

2017 ◽  
Vol 29 (3) ◽  
pp. 1041-1048 ◽  
Author(s):  
Sven Enerbäck ◽  
Daniel Nilsson ◽  
Noel Edwards ◽  
Mikael Heglind ◽  
Sumaya Alkanderi ◽  
...  
Keyword(s):  
Dna Binding ◽  
Inner Ear ◽  
Renal Tubular Acidosis ◽  
Cultured Cells ◽  
Collecting Duct ◽  
Sensorineural Deafness ◽  
Distal Renal Tubular Acidosis ◽  
Acid Base ◽  
Recessive Mutations ◽  
Renal Tubular

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in FOXI1 (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.

Mutations in the band 3 (AE1) gene associated with distal renal tubular acidosis

2001 ◽  
Vol 29 (3) ◽  
pp. A87-A87
Author(s):  
A. M. Toye ◽  
L. J. Bruce ◽  
O. Wrong ◽  
M. T. Young ◽  
R. J. Unwin ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Renal Tubular

scholarly journals Deletion of hensin/DMBT1 blocks conversion of  - to  -intercalated cells and induces distal renal tubular acidosis

2010 ◽  
Vol 107 (50) ◽  
pp. 21872-21877 ◽  
Author(s):  
X. Gao ◽  
D. Eladari ◽  
F. Leviel ◽  
B. Y. Tew ◽  
C. Miro-Julia ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Distal Renal Tubular Acidosis ◽  
Intercalated Cells ◽  
Renal Tubular

Band 3 nullVIENNA, a novel homozygousSLC4A1p.Ser477X variant causing severe hemolytic anemia, dyserythropoiesis and complete distal renal tubular acidosis

2016 ◽  
Vol 64 (3) ◽  
pp. e26227 ◽  
Author(s):  
Leo Kager ◽  
Lesley J. Bruce ◽  
Petra Zeitlhofer ◽  
Joanna F. Flatt ◽  
Tabita M. Maia ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Renal Tubular Acidosis ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Renal Tubular

Cellular response to acute respiratory acidosis in rat medullary collecting duct

1983 ◽  
Vol 245 (6) ◽  
pp. F670-F679 ◽  
Author(s):  
K. M. Madsen ◽  
C. C. Tisher
Keyword(s):  
Plasma Membrane ◽  
Surface Density ◽  
Collecting Duct ◽  
Respiratory Acidosis ◽  
Hydrogen Ion ◽  
Apical Plasma Membrane ◽  
Apical Region ◽  
Intercalated Cells ◽  
Ion Secretion ◽  
Medullary Collecting Duct

The collecting duct of the mammalian kidney is involved in urine acidification. Recent studies in the turtle bladder suggest that hydrogen ion secretion in response to elevated CO2 is regulated by insertion of hydrogen pumps into the luminal membrane of the mitochondria-rich cells. Because intercalated cells of the collecting duct are structurally similar to mitochondria-rich cells of the amphibian bladder, we studied the rat outer medullary collecting duct (OMCD) during respiratory acidosis to determine whether changes compatible with hydrogen ion secretion occur in the intercalated cells. Rats were studied during normal acid-base conditions and after 4-5 h of respiratory acidosis. After collection of physiologic data, the kidneys were fixed by in vivo perfusion and processed for electron microscopy. No changes were observed in the principal cells of the OMCD. Morphometric analysis revealed a significant increase in the surface density of the apical plasma membrane and a decrease in the number of tubulovesicular profiles in the apical region of the intercalated cells throughout the OMCD with respiratory acidosis. There were no changes in surface density of the basolateral membrane. These findings suggest that in response to respiratory acidosis there is transport of membrane from the tubulovesicular membrane compartment to the apical plasma membrane of the intercalated cells.

scholarly journals Autosomal Dominant Distal Renal Tubular Acidosis Is Associated in Three Families with Heterozygosity for the R589H Mutation in the AE1 (Band 3) Cl−/HCO3−Exchanger

1998 ◽  
Vol 273 (11) ◽  
pp. 6380-6388 ◽  
Author(s):  
Petr Jarolim ◽  
Chairat Shayakul ◽  
Daniel Prabakaran ◽  
Lianwei Jiang ◽  
Alan Stuart-Tilley ◽  
...  
Keyword(s):  
Renal Tubular Acidosis ◽  
Autosomal Dominant ◽  
Band 3 ◽  
Distal Renal Tubular Acidosis ◽  
Renal Tubular
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