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Kidney Week

Abstract: FR-PO1113

Differential Control of COX-2 Expression in Macula Densa Cells Under Calcineurin Inhibition by Cyclosporine A

Session Information

  • Transplantation: Basic
    November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 1901 Transplantation: Basic


  • Hu, Junda, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • Xu, Yan, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • Mutig, Kerim, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • Bachmann, Sebastian, Charité-Universitätsmedizin Berlin, Berlin, Germany

Group or Team Name

  • Institut fuer Vegetative Anatomie

Calcineurin inhibitors such as cyclosporine A (CsA) are in use as immunosuppressive drugs to prevent rejection of transplanted organs. Despite positive outcomes, side effects such as decreased GFR and overall functional and structural deterioration may affect the kidney. Among the causes, interactions of vasoactive systems have been considered. We therefore studied how CsA may cause dysregulation of key juxtagomerular signaling components.


Wistar rats received vehicle or 25mg CsA/kg b.w./d for 14d. Organs were perfusion-fixed and embedded for morphology. Cultured macula densa (MD) cells were treated with CsA (5 µM) and angiotensin II (AngII; 1 µM) for 6 or 24h. Tissues or cells were immunohistochemically studied for renin, COX-2, NFAT subtypes 1 to 4, p38 MAPK, CREB, NF-kB, and activating p38 MAPK and CREB phosphorylation. Inhibitors to p38 MAPK (SB203580; 10 µM) and NF-kB (Bay 11-7082; 5 µM) were applied in cells. Cells were also analyzed by PCR and Western blot.


CsA caused the known upregulation of renin and complete downregulation of COX-2. An assumed link between NFAT and COX-2 within MD could not be established. In MD cells, CsA caused a rise in COX-2 abundance at 6 and 24 h (2-fold each); p38 MAPK phosphorylation was increased in parallel (1.9-fold). Inhibition of p38 MAPK attenuated CsA-induced COX-2 upregulation by 50%. Under the same conditions, NF-kB showed nuclear translocation (+50%). Inhibitor to NF-kB (6h) blunted COX-2 stimulation by 35%. CREB phosphorylation was increased 2- to 4-fold with COX-2 stimulation (6h). AngII substantially decreased expression of baseline COX-2 by 40% (6h) and blunted CsA-induced COX-2 stimulation by 30% (6h). All data were significant (min. p<0.05).


In sum, calcineurin inhibition by CsA in vivo suppressed juxtaglomerular COX-2 independently of NFAT signaling. Contrastingly, cultured MD cells show substantial stimulation of COX-2 upon CsA, involving MAPK, NF-kB, and CREB. Dominant, antagonistic AngII is likely to act on the same signaling cascade. This novel, MD cell-specific regulatory synergism of calcineurin and angiotensin, governing COX-2 biosynthesis, may serve to address juxtaglomerular dysregulation under CsA treatment.


  • Government Support - Non-U.S.