title: Cyclosporin A produces distal renal tubular acidosis by blocking peptidyl prolyl cis-trans isomerase activity of cyclophilin.
abstract: 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.
authors.affiliation: Department of Pediatrics, Strong Children's Research Center, University of Rochester School of Medicine, Rochester, NY 14642, USA.
authors.forename: Seiji
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsuruoka
authors.forename: Soundarapandian
authors.initials: S
authors.lastname: Vijayakumar
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Yixin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Akio
authors.initials: A
authors.lastname: Fujimura
authors.forename: Qais
authors.initials: Q
authors.lastname: Al-Awqati
authors.forename: George J
authors.initials: GJ
authors.lastname: Schwartz
mesh_terms: D000141:Acidosis, Renal Tubular / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D000818:Animals; D027963:Chloride-Bicarbonate Antiporters / Q000187:drug effects; D021983:Cyclophilins / Q000037:antagonists & inhibitors*; D016572:Cyclosporine / Q000633:toxicity*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D016326:Extracellular Matrix Proteins; D005260:Female; D006863:Hydrogen-Ion Concentration; D007166:Immunosuppressive Agents / Q000633:toxicity*; D066298:In Vitro Techniques; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000502:physiology; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000502:physiology; D011817:Rabbits; D011971:Receptors, Immunologic / Q000378:metabolism / Q000502:physiology; D051116:Receptors, Scavenger
chemical_list: D027963:Chloride-Bicarbonate Antiporters; D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; C495130:hensin protein, rabbit; D016572:Cyclosporine; D021983:Cyclophilins