The calcineurin inhibitor cyclosporine A activates the renal Na-(K)-Cl cotransporters via local and systemic mechanisms
type: CreativeWork
description: The two calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus are potent immunosuppressive drugs that have become indispensable in the post-transplantational therapy and in the treatment of autoimmune diseases. Immunosuppression via CNIs is achieved by inhibition of the calcineurin phosphatase and thus blocking the signaling pathway of NFAT (nuclear factor of activated T cells), thereby inhibiting T cell immune response. However, chronic use of CNIs is complicated by serious side effects which particularly affect the kidney, reflected by a large number of patients who develop electrolyte disorders, hypertension and renal failure under CNI treatment. The mechanisms of CNI-induced salt retention and hypertension are complex, involving not only intraepithelial but also systemic effects. Since calcineurin inhibition is associated with activation of the renal Na+-K+-2Cl- cotransporter (NKCC2) and the Na+-Cl-cotransporter (NCC) that are expressed in the thick ascending limb (TAL) and the distal convoluted tubule (DCT) of the nephron, respectively, it has been suggested that the calcineurin phosphatase is involved in the regulation of the salt transporters. Interestingly, previous studies have demonstrated that CsA increases both NKCC2 and NCC activity, whereas tacrolimus merely stimulates NCC function. This study aimed to unravel the local and systemic mechanisms underlying calcineurin inhibition that lead to salt retention and hypertension. We found that key proteins involved in calcineurin inhibition and the activation of NKCC2 and NCC are ubiquitously expressed along TAL and DCT. These results indicate that the distinct effects of CsA and tacrolimus on the activation of the salt transporters do not arise from differential expression of these key proteins, so that systemic mechanims might play a role. Thus, we sought to differentiate between local and systemic effects of CsA treatment by applying short- and long-term treatment protocols in vivo and in vitro.…
abstract: The two calcineurin inhibitors (CNIs) cyclosporine A (CsA) and tacrolimus are potent immunosuppressive drugs that have become indispensable in the post-transplantational therapy and in the treatment of autoimmune diseases. Immunosuppression via CNIs is achieved by inhibition of the calcineurin phosphatase and thus blocking the signaling pathway of NFAT (nuclear factor of activated T cells), thereby inhibiting T cell immune response. However, chronic use of CNIs is complicated by serious side effects which particularly affect the kidney, reflected by a large number of patients who develop electrolyte disorders, hypertension and renal failure under CNI treatment. The mechanisms of CNI-induced salt retention and hypertension are complex, involving not only intraepithelial but also systemic effects. Since calcineurin inhibition is associated with activation of the renal Na+-K+-2Cl- cotransporter (NKCC2) and the Na+-Cl-cotransporter (NCC) that are expressed in the thick ascending limb (TAL) and the distal convoluted tubule (DCT) of the nephron, respectively, it has been suggested that the calcineurin phosphatase is involved in the regulation of the salt transporters. Interestingly, previous studies have demonstrated that CsA increases both NKCC2 and NCC activity, whereas tacrolimus merely stimulates NCC function. This study aimed to unravel the local and systemic mechanisms underlying calcineurin inhibition that lead to salt retention and hypertension. We found that key proteins involved in calcineurin inhibition and the activation of NKCC2 and NCC are ubiquitously expressed along TAL and DCT. These results indicate that the distinct effects of CsA and tacrolimus on the activation of the salt transporters do not arise from differential expression of these key proteins, so that systemic mechanims might play a role. Thus, we sought to differentiate between local and systemic effects of CsA treatment by applying short- and long-term treatment protocols in vivo and in vitro.…
author: Blankenstein, Katharina Ilse
language: en
license: https://creativecommons.org/licenses/by/4.0/
date published: 2019
date modified: 2026-07-27T21:28:37Z
provider: Technische Universität Berlin
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Technische Universität Berlin

PropertyValue
property ID: DOI
value: 10.14279/depositonce-8697