Cyclosporine A Suppresses Cyclooxygenase-2 Expression in the Rat Kidney

Abstract

Abstract. On the basis of recent evidence that the cyclooxygenase-2 (COX-2) gene promoter contains functional binding sites for the nuclear factor of activated T cells (NFAT) and that COX-2 is expressed in a regulated fashion in the kidney, this study aimed to assess the effect of immunosuppressants on COX-2 expression in the kidney. Therefore, Wistar-Kyoto rats were treated with cyclosporine A (CsA; 15 mg/kg per day) or tacrolimus (5 mg/kg per day) for 7 d each. Both drugs markedly lowered COX-2 expression while COX-1 expression remained unaltered. Furthermore, CsA blunted the increase of renocortical COX-2 expression in response to low salt intake or a combination of low-salt diet with the ACE inhibitor ramipril (10 mg/kg per day), which strongly stimulates renocortical COX-2 expression. At the same time, calcineurin inhibitors moderately enhanced basal as well as stimulated renin secretion and renin gene expression. These findings suggest that inhibition of calcineurin could be a crucial determinant for the regulated expression of COX-2 in the kidney. Inhibition of COX-2 expression may therefore at least in part account for the well-known adverse effects of immunosuppressants in the kidney. Moreover, our data suggest that the stimulation of the renin system by low salt and by ACE inhibitors is not essentially mediated by COX-2 activity.The family of cyclooxygenases (COX)

Calcium-sensing receptor signaling pathways in medullary thick ascending limb cells mediate COX-2-derived PGE2production: functional significance

“…Previous work demonstrated that COX-2 expression in the outer medulla of the kidney is CaN dependent; however, the cell type in which this occurred was not identified (30). We determined whether CaN/NFAT signaling mediates CaR-mediated COX-2 expression in mTAL cells.…”

Calcineurin and Sorting-Related Receptor with A-Type Repeats Interact to Regulate the Renal Na+-K+-2Cl− Cotransporter

“…Calcineurin, a ubiquitously expressed calcium-/calmodulin-dependent serine-threonine phosphatase, has been shown to play a role in the context of TAL function. [6][7][8][9][10][11] Calcineurin inhibitors are widely used as immunosuppressive drugs and have undisputed benefits in decreasing rejection rates after transplantation, but also have major side effects including hypertension. Their systemic effects on the sympathetic nervous system or the renin-angiotensin-aldosterone axis have been described, but much less information is known about the cellular mechanisms of calcineurin-dependent regulation of renal transporters.…”

“…Their systemic effects on the sympathetic nervous system or the renin-angiotensin-aldosterone axis have been described, but much less information is known about the cellular mechanisms of calcineurin-dependent regulation of renal transporters. [10][11][12] We have recently shown that the calcineurin inhibitor tacrolimus caused salt retention and hypertension in mice. 13 These effects were largely mediated by increased phosphorylation and activity of the renal thiazidesensitive Na + -Cl 2 -cotransporter (NCC) of the distal convoluted tubule (DCT).…”

Genomic Profiling of Kidney Ischemia-Reperfusion Reveals Expression of Specific Alloimmunity-Associated Genes: Linking “Immune” and “Nonimmune” Injury Events

“…This gene is coding for inflammatory regulator cyclooxygenase-2 (COX-2) and expressed in a regulated fashion in the kidney. The recent discovery of the binding site for the nuclear factor of activated T cells (NFAT), the member of calcineurin pathway (Figure 1) explains inhibition of COX-2 by Tacrolimus (28). The evaluation of these novel IRI-affected candidate genes and dissection of their corresponding pathways can lead to new approaches by which improved management of early "non-immune" transplant events can decrease susceptibility to more classic "immune" changes and CAN.…”