Document Detail

The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins.
MedLine Citation:
PMID:  19439519     Owner:  NLM     Status:  MEDLINE    
Calcineurin inhibitors like FK506 (tacrolimus) are routinely used for immunosuppression following transplantation. Its use is limited by many side effects, including renal tubular acidosis (RTA), mainly of the distal type. In this study, rats were treated with FK506 and at baseline (after 9 days) systemic acid-base status was similar to that in control animals. However, FK506-treated rats given NH(4)Cl in the drinking water for 2 days developed a more severe metabolic acidosis than control animals. Urine pH was more alkaline, but net acid excretion was normal. After 7 days of acid load, all differences related to acid-base homeostasis were equalized in both groups. Protein abundance of type IIa Na-P(i) cotransporter, type 3 Na(+)/H(+) exchanger, and electrogenic Na(+)-bicarbonate cotransporter, and both a4 and B2 subunits of the vacuolar H(+)-ATPase were reduced under baseline conditions, while induction of metabolic acidosis enhanced protein abundance of these transporters in FK506-treated animals. In parallel, protein expression of AE1 was reduced at baseline and increased together with pendrin during NH(4)Cl loading in FK506 rats. Protein abundance of the Na(+)-bicarbonate cotransporter NBCn1 was reduced under baseline conditions but remained downregulated during metabolic acidosis. Morphological analysis revealed an increase in the relative number of non-type A intercalated cells in the connecting tubule and cortical collecting duct at the expense of principal cells. Additionally, subcellular distribution of the a4 subunit of the vacuolar H(+)-ATPase was affected by FK506 with less luminal localization in the connecting tubule and outer medullary collecting duct. These data suggest that FK506 impacts on several major acid-base transport proteins in the kidney, and its use is associated with transient metabolic acidosis and altered expression of key renal acid-base transport proteins.
Nilufar Mohebbi; Marija Mihailova; Carsten A Wagner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-13
Journal Detail:
Title:  American journal of physiology. Renal physiology     Volume:  297     ISSN:  1522-1466     ISO Abbreviation:  Am. J. Physiol. Renal Physiol.     Publication Date:  2009 Aug 
Date Detail:
Created Date:  2009-07-24     Completed Date:  2009-08-27     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:  F499-509     Citation Subset:  IM    
Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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MeSH Terms
Acid-Base Equilibrium / drug effects*
Acidosis, Renal Tubular / chemically induced*,  enzymology,  pathology
Ammonium Chloride
Anion Exchange Protein 1, Erythrocyte / metabolism
Biological Markers / blood,  urine
Calcineurin / antagonists & inhibitors*,  metabolism
Chloride-Bicarbonate Antiporters / metabolism
Disease Models, Animal
Enzyme Inhibitors / administration & dosage,  toxicity*
Injections, Subcutaneous
Membrane Transport Proteins / metabolism*
Nephrons / drug effects*,  enzymology,  pathology
Rats, Wistar
Severity of Illness Index
Sodium-Bicarbonate Symporters / metabolism
Sodium-Hydrogen Antiporter / metabolism
Sodium-Phosphate Cotransporter Proteins, Type IIa / metabolism
Tacrolimus / administration & dosage,  toxicity*
Vacuolar Proton-Translocating ATPases / metabolism
Reg. No./Substance:
0/Anion Exchange Protein 1, Erythrocyte; 0/Biological Markers; 0/Chloride-Bicarbonate Antiporters; 0/Enzyme Inhibitors; 0/Membrane Transport Proteins; 0/Slc34a1 protein, rat; 0/Slc4a7 protein, rat; 0/Sodium-Bicarbonate Symporters; 0/Sodium-Hydrogen Antiporter; 0/Sodium-Phosphate Cotransporter Proteins, Type IIa; 0/pendrin protein, rat; 0/sodium-hydrogen exchanger 3; 109581-93-3/Tacrolimus; 12125-02-9/Ammonium Chloride; EC; EC 3.6.1.-/Vacuolar Proton-Translocating ATPases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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