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Am J Physiol Renal Physiol (September 7, 2004). doi:10.1152/ajprenal.00218.2004
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Submitted on June 14, 2004
Accepted on September 1, 2004

Cyclosporin A Produces Distal Renal Tubular Acidosis by Blocking Peptidyl Prolyl cis-trans Isomerase Activity of Cyclophilin

Seiji Watanabe1, Suichi Tsuruoka2, Soundarapandian Vijayakumar3, Gunter Fischer4, Yixin Zhang4, Akio Fujimura2, Qais Al-Awqati3, and George J. Schwartz1*

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

* To whom correspondence should be addressed. E-mail: George_Schwartz{at}urmc.rochester.edu.

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 activity (PPIase) of cyclophilin A. We studied HCO3- transport and changes in {beta}-intercalated cell pH upon luminal Cl- removal in isolated perfused rabbit cortical collecting tubules (CCDs) before and after exposure to media pH 6.8 for 3 hrs. 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 HCO3- secretory flux, estimated as the difference between net flux and that after Cl- removal from lumen, was -6.7±0.2 pmol/min/mm 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 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 {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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