ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

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

Authors

  • 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
Background

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.

Methods

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.

Results

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.

Conclusion

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.

Funding

  • Government Support - Non-U.S.