Document Detail

Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin.
MedLine Citation:
PMID:  15353404     Owner:  NLM     Status:  MEDLINE    
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.
Seiji Watanabe; Shuichi Tsuruoka; Soundarapandian Vijayakumar; Gunter Fischer; Yixin Zhang; Akio Fujimura; Qais Al-Awqati; George J Schwartz
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-09-07
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  288     ISSN:  1931-857X     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2005 Jan 
Date Detail:
Created Date:  2004-12-07     Completed Date:  2005-03-04     Revised Date:  2011-04-28    
Medline Journal Info:
Nlm Unique ID:  100901990     Medline TA:  Am J Physiol Renal Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  F40-7     Citation Subset:  IM    
Department of Pediatrics, Strong Children's Research Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
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MeSH Terms
Acidosis, Renal Tubular / chemically induced*,  enzymology,  metabolism
Chloride-Bicarbonate Antiporters / drug effects
Cyclophilins / antagonists & inhibitors*
Cyclosporine / toxicity*
Extracellular Matrix / drug effects,  metabolism,  physiology
Extracellular Matrix Proteins
Hydrogen-Ion Concentration
Immunosuppressive Agents / toxicity*
Kidney Tubules, Collecting / drug effects,  physiology
Kidney Tubules, Distal / drug effects*,  physiology
Receptors, Immunologic / metabolism,  physiology
Receptors, Scavenger
Grant Support
Reg. No./Substance:
0/Chloride-Bicarbonate Antiporters; 0/Extracellular Matrix Proteins; 0/Immunosuppressive Agents; 0/Receptors, Immunologic; 0/Receptors, Scavenger; 0/hensin protein, rabbit; 59865-13-3/Cyclosporine; EC 5.2.1.-/Cyclophilins

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