The calcineurin inhibitor FK506 (tacrolimus) is associated with transient metabolic acidosis and altered expression of renal acid-base transport proteins.
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.
Institute of Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
Nilufar
N
Mohebbi
Marija
M
Mihailova
Carsten A
CA
Wagner
D000136:Acid-Base Equilibrium / Q000187:drug effects*; D000141:Acidosis, Renal Tubular / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D000643:Ammonium Chloride; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000378:metabolism; D015415:Biomarkers / Q000097:blood / Q000652:urine; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D027963:Chloride-Bicarbonate Antiporters / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D007279:Injections, Subcutaneous; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009399:Nephrons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D000076988:Sulfate Transporters; D016559:Tacrolimus / Q000008:administration & dosage / Q000633:toxicity*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
D001457:Anion Exchange Protein 1, Erythrocyte; D015415:Biomarkers; D065095:Calcineurin Inhibitors; D027963:Chloride-Bicarbonate Antiporters; D004791:Enzyme Inhibitors; D026901:Membrane Transport Proteins; C494615:Slc26A4 protein, rat; C493556:Slc34a1 protein, rat; C498902:Slc4a7 protein, rat; D027982:Sodium-Bicarbonate Symporters; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D000076988:Sulfate Transporters; D000643:Ammonium Chloride; D019703:Calcineurin; D025262:Vacuolar Proton-Translocating ATPases; D016559:Tacrolimus