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

¹Department of Pediatrics, Strong Children's Research Center, University of Rochester School of Medicine, Rochester; ²Department of Clinical Pharmacology, Jichi Medical School, Minamikawachi, Tochigi, Japan; ³Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, New York; and ⁴Max Planck Research Unit for Enzymology of Protein Folding, Halle/Saale, Germany

Submitted 14 June 2004 ; accepted in final form 1 September 2004

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 -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 -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 -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 -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.

bicarbonate secretion; cell pH; intercalated cell; hensin; cortical collecting duct

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