Source:http://linkedlifedata.com/resource/pubmed/id/15353404
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Predicate | Object |
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
1
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pubmed:dateCreated |
2004-12-7
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pubmed:abstractText |
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 HCO(3)(-) transport and changes in beta-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 beta-intercalated cells by extracellular deposition of hensin (J Clin Invest 109: 89, 2002). Here, CsA prevented this adaptation. The unidirectional HCO(3)(-) 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 HCO(3)(-) secretion and apical Cl(-):HCO(3)(-) 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 HCO(3)(-) 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(-):HCO(3)(-) exchange. Acid incubation resulted in prominent "clumpy" staining of extracellular hensin and diminished apical surface of beta-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 beta-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.
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pubmed:grant | |
pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Chloride-Bicarbonate Antiporters,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclophilins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclosporine,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Matrix Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Immunosuppressive Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Immunologic,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Scavenger,
http://linkedlifedata.com/resource/pubmed/chemical/hensin protein, rabbit
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1931-857X
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:volume |
288
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
F40-7
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pubmed:dateRevised |
2011-4-28
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pubmed:meshHeading |
pubmed-meshheading:15353404-Acidosis, Renal Tubular,
pubmed-meshheading:15353404-Animals,
pubmed-meshheading:15353404-Chloride-Bicarbonate Antiporters,
pubmed-meshheading:15353404-Cyclophilins,
pubmed-meshheading:15353404-Cyclosporine,
pubmed-meshheading:15353404-Extracellular Matrix,
pubmed-meshheading:15353404-Extracellular Matrix Proteins,
pubmed-meshheading:15353404-Female,
pubmed-meshheading:15353404-Hydrogen-Ion Concentration,
pubmed-meshheading:15353404-Immunosuppressive Agents,
pubmed-meshheading:15353404-Kidney Tubules, Collecting,
pubmed-meshheading:15353404-Kidney Tubules, Distal,
pubmed-meshheading:15353404-Rabbits,
pubmed-meshheading:15353404-Receptors, Immunologic,
pubmed-meshheading:15353404-Receptors, Scavenger
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pubmed:year |
2005
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pubmed:articleTitle |
Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin.
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pubmed:affiliation |
Department of Pediatrics, Strong Children's Research Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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