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

Am J Physiol Renal Physiol. 2005 Jan;288(1):F40-7. doi: 10.1152/ajprenal.00218.2004. Epub 2004 Sep 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acidosis, Renal Tubular / chemically induced*
  • Acidosis, Renal Tubular / enzymology
  • Acidosis, Renal Tubular / metabolism
  • Animals
  • Chloride-Bicarbonate Antiporters / drug effects
  • Cyclophilins / antagonists & inhibitors*
  • Cyclosporine / toxicity*
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / metabolism
  • Extracellular Matrix / physiology
  • Extracellular Matrix Proteins
  • Female
  • Hydrogen-Ion Concentration
  • Immunosuppressive Agents / toxicity*
  • In Vitro Techniques
  • Kidney Tubules, Collecting / drug effects
  • Kidney Tubules, Collecting / physiology
  • Kidney Tubules, Distal / drug effects*
  • Kidney Tubules, Distal / physiology
  • Rabbits
  • Receptors, Immunologic / metabolism
  • Receptors, Immunologic / physiology
  • Receptors, Scavenger


  • Chloride-Bicarbonate Antiporters
  • Extracellular Matrix Proteins
  • Immunosuppressive Agents
  • Receptors, Immunologic
  • Receptors, Scavenger
  • hensin protein, rabbit
  • Cyclosporine
  • Cyclophilins