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J Am Soc Nephrol. 2014 Jul;25(7):1474-85. doi: 10.1681/ASN.2013070679. Epub 2014 Feb 7.

Epac-Rap signaling reduces oxidative stress in the tubular epithelium.

Author information

  • 1Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands;
  • 2Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands;
  • 3LinXis B.V., Amsterdam, The Netherlands;
  • 4Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands;
  • 5Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands;
  • 6BIOLOG Life Science Institute, Bremen, Germany; and.
  • 7Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands; OcellO BV, Leiden, The Netherlands.


Activation of Rap1 by exchange protein activated by cAMP (Epac) promotes cell adhesion and actin cytoskeletal polarization. Pharmacologic activation of Epac-Rap signaling by the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP during ischemia-reperfusion (IR) injury reduces renal failure and application of 8-pCPT-2'-O-Me-cAMP promotes renal cell survival during exposure to the nephrotoxicant cisplatin. Here, we found that activation of Epac by 8-pCPT-2'-O-Me-cAMP reduced production of reactive oxygen species during reoxygenation after hypoxia by decreasing mitochondrial superoxide production. Epac activation prevented disruption of tubular morphology during diethyl maleate-induced oxidative stress in an organotypic three-dimensional culture assay. In vivo renal targeting of 8-pCPT-2'-O-Me-cAMP to proximal tubules using a kidney-selective drug carrier approach resulted in prolonged activation of Rap1 compared with nonconjugated 8-pCPT-2'-O-Me-cAMP. Activation of Epac reduced antioxidant signaling during IR injury and prevented tubular epithelial injury, apoptosis, and renal failure. Our data suggest that Epac1 decreases reactive oxygen species production by preventing mitochondrial superoxide formation during IR injury, thus limiting the degree of oxidative stress. These findings indicate a new role for activation of Epac as a therapeutic application in renal injury associated with oxidative stress.

Copyright © 2014 by the American Society of Nephrology.

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