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Kidney Week

Abstract: PO1406

Angiotensin II Receptor Blockade Alleviates Calcineurin Inhibitor Nephrotoxicity by Restoring p38 MAPK/NF-kB/COX-2 Signaling in Kidney Cortex

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic


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

Immunosuppression based on calcineurin inhibitors (CNI) such as cyclosporine A (CsA) is the current standard for patients undergoing organ transplantation. Nephrotoxic side effects of CNI include reduction of renal cortical cyclooxygenase 2 (COX-2) expression along with pathophysiological alterations of glomerular filtration rate and sodium balance. The underlying molecular mechanisms are poorly understood. Since CNI stimulate the renin-angiotensin system (RAS), we hypothesized that the suppression of COX-2 is related to enhanced RAS activity.


To test this hypothesis, short- (3 days) and long-term effects (3 weeks) of CsA (25mg/kg*d), candesartan (5mg/kg*d), celecoxib (50 mg/kg*d) or their combinations were evaluated in Wistar rats to monitor COX-2 and RAS, as well as kidney physiology, morphology and biochemistry. Cultured macula densa (MD) cells were treated with CsA, angiotensin II (Ang II), p38 MAPK inhibitor or NF-kB inhibitor in various combinations to reveal molecular pathways mediating effects of RAS on COX-2.


Inhibition of calcineurin in cultured MD cells using CsA or siRNA increased COX-2 activity via stimulation of p38 MAPK and NF-kB. Concomitant application of Ang II abolished these effects suggesting a dominant role for RAS. In rats, 3 days and 3 weeks CsA treatments led to increased renin biosynthesis, decreased cortical COX-2 expression, reduced creatinine clearance, and sodium retention due to activation of major distal salt transporters, NKCC2 and NCC. These deteriorations were partially or completely normalized by simultaneous administration of a RAS inhibitor candesartan for 3 days or 3 weeks, respectively. In contrast, administration of a selective COX-2 inhibitor, celecoxib, largely recapitulated effects of CsA and significantly reduced the beneficial effects of candesartan by concomitant drug application. Therefore, COX-2 suppression is a major factor contributing to CNI nephrotoxicity.


In summary, the present study established calcineurin as an endogenous COX-2 inhibitor, acting via suppression of p38 MAPK and NF-kB activity in MD cells. CNI-induced RAS activation critically reduces cortical COX-2 activity, thus overriding local stimulatory effects of calcineurin inhibition. Our data support the use of RAS inhibitors for alleviation of CNI nephrotoxicity.


  • Government Support - Non-U.S.