title: Calcineurin inhibitor cyclosporine A activates renal Na-K-Cl cotransporters via local and systemic mechanisms.
abstract: Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany.
authors.forename: K I
authors.identifier: 0000-0001-5528-2808
authors.initials: KI
authors.lastname: Blankenstein
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Borschewski
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Labes
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Paliege
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Boldt
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health & Science University and Veterans Affairs Medical Center, Portland, Oregon; and.
authors.forename: J A
authors.initials: JA
authors.lastname: McCormick
authors.affiliation: Division of Nephrology and Hypertension, Oregon Health & Science University and Veterans Affairs Medical Center, Portland, Oregon; and.
authors.forename: D H
authors.initials: DH
authors.lastname: Ellison
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bader
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bachmann
authors.affiliation: Department of Anatomy, Charité University Medicine, Berlin, Germany; kerim.mutig@charite.de.
authors.forename: K
authors.initials: K
authors.lastname: Mutig
mesh_terms: D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D065095:Calcineurin Inhibitors / Q000633:toxicity*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016572:Cyclosporine / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008138:Loop of Henle / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011910:Rats, Brattleboro; D017208:Rats, Wistar; D012083:Renin / Q000378:metabolism; D064466:Solute Carrier Family 12, Member 1 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D064486:Solute Carrier Family 12, Member 3 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014882:Water-Electrolyte Balance / Q000187:drug effects
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C578716:Slc12a1 protein, rat; C578876:Slc12a3 protein, rat; D064466:Solute Carrier Family 12, Member 1; D064486:Solute Carrier Family 12, Member 3; D001127:Arginine Vasopressin; D016572:Cyclosporine; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D012083:Renin
keywords: hypertension; salt transport; sodium-chloride cotransporter; sodium-potassium-chloride cotransporter; vasopressin