Calcineurin inhibitor cyclosporine A activates renal NA-K-CL cotransporters via local and systemic mechanisms

K. I. Blankenstein, A. Borschewski, R. Labes, A. Paliege, C. Boldt, J. A. McCormick, D. H. Ellison, M. Bader, S. Bachmann, K. Mutig

Research output: Contribution to journalArticle

17 Scopus citations

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 endoge-nously 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.

Original languageEnglish (US)
Pages (from-to)F489-F501
JournalAmerican Journal of Physiology - Renal Physiology
Volume312
Issue number3
DOIs
StatePublished - Mar 2017

Keywords

  • Hypertension
  • Salt transport
  • Sodium-chloride cotransporter
  • Sodium-potassium-chlo-ride cotransporter
  • Vasopressin

ASJC Scopus subject areas

  • Physiology
  • Urology

Fingerprint Dive into the research topics of 'Calcineurin inhibitor cyclosporine A activates renal NA-K-CL cotransporters via local and systemic mechanisms'. Together they form a unique fingerprint.

  • Cite this