Epac-Rap signaling reduces oxidative stress in the tubular epithelium

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 appl...

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Veröffentlicht in:	Journal of the American Society of Nephrology Jg. 25; H. 7; S. 1474
Hauptverfasser:	Stokman, Geurt, Qin, Yu, Booij, Tijmen H, Ramaiahgari, Sreenivasa, Lacombe, Marie, Dolman, M Emmy M, van Dorenmalen, Kim M A, Teske, Gwendoline J D, Florquin, Sandrine, Schwede, Frank, van de Water, Bob, Kok, Robbert J, Price, Leo S
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 01.07.2014
Schlagworte:	Animals Cyclic AMP - analogs & derivatives Cyclic AMP - pharmacology Guanine Nucleotide Exchange Factors - drug effects Guanine Nucleotide Exchange Factors - physiology Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - metabolism Male Mice Mice, Inbred C57BL Oxidative Stress Signal Transduction Urothelium - drug effects Urothelium - metabolism
ISSN:	1533-3450, 1533-3450
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Abstract	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.
AbstractList	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. 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.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.
Author	Schwede, Frank Teske, Gwendoline J D Booij, Tijmen H Ramaiahgari, Sreenivasa Qin, Yu Kok, Robbert J Dolman, M Emmy M Stokman, Geurt Lacombe, Marie Price, Leo S Florquin, Sandrine van Dorenmalen, Kim M A van de Water, Bob
Author_xml	– sequence: 1 givenname: Geurt surname: Stokman fullname: Stokman, Geurt email: g.stokman@amc.uva.nl organization: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands; g.stokman@amc.uva.nl – sequence: 2 givenname: Yu surname: Qin fullname: Qin, Yu organization: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands – sequence: 3 givenname: Tijmen H surname: Booij fullname: Booij, Tijmen H organization: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands – sequence: 4 givenname: Sreenivasa surname: Ramaiahgari fullname: Ramaiahgari, Sreenivasa organization: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands – sequence: 5 givenname: Marie surname: Lacombe fullname: Lacombe, Marie organization: LinXis B.V., Amsterdam, The Netherlands – sequence: 6 givenname: M Emmy M surname: Dolman fullname: Dolman, M Emmy M organization: Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands – sequence: 7 givenname: Kim M A surname: van Dorenmalen fullname: van Dorenmalen, Kim M A organization: Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands – sequence: 8 givenname: Gwendoline J D surname: Teske fullname: Teske, Gwendoline J D organization: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands – sequence: 9 givenname: Sandrine surname: Florquin fullname: Florquin, Sandrine organization: Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands – sequence: 10 givenname: Frank surname: Schwede fullname: Schwede, Frank organization: BIOLOG Life Science Institute, Bremen, Germany; and – sequence: 11 givenname: Bob surname: van de Water fullname: van de Water, Bob organization: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands – sequence: 12 givenname: Robbert J surname: Kok fullname: Kok, Robbert J organization: Department of Pharmaceutics, Utrecht University, Utrecht, The Netherlands – sequence: 13 givenname: Leo S surname: Price fullname: Price, Leo S organization: Division of Toxicology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands; OcellO BV, Leiden, The Netherlands
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SubjectTerms	Animals Cyclic AMP - analogs & derivatives Cyclic AMP - pharmacology Guanine Nucleotide Exchange Factors - drug effects Guanine Nucleotide Exchange Factors - physiology Kidney Tubules, Proximal - drug effects Kidney Tubules, Proximal - metabolism Male Mice Mice, Inbred C57BL Oxidative Stress Signal Transduction Urothelium - drug effects Urothelium - metabolism
Title	Epac-Rap signaling reduces oxidative stress in the tubular epithelium
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