Epac-rap signaling reduces oxidative stress in the tubular epithelium
| Autor: | 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., Sub Drug delivery, Pharmaceutics |
|---|---|
| Přispěvatelé: | Amsterdam institute for Infection and Immunity, Pathology, Oncology, Sub Drug delivery, Pharmaceutics |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
antioxidant cisplatin reactive oxygen metabolite medicine.disease_cause Kidney Tubules Proximal Mice chemistry.chemical_compound reoxygenation morphology Cyclic AMP kidney cell Guanine Nucleotide Exchange Factors oxidative stress drug carrier chemistry.chemical_classification Kidney Superoxide apoptosis General Medicine reperfusion injury Cell biology medicine.anatomical_structure Biochemistry Nephrology kidney injury superoxide Signal transduction actin Signal Transduction kidney injury antiporter Biology cell survival kidney proximal tubule medicine Animals Cell adhesion Reactive oxygen species polarization hypoxia cell adhesion assay medicine.disease kidney failure Mice Inbred C57BL Basic Research chemistry Apoptosis exposure Urothelium epithelium Reperfusion injury Oxidative stress |
| Zdroj: | Journal of the American Society of Nephrology, 25(7), 1474-1485. American Society of Nephrology Journal of the American Society of Nephrology, 25(7), 1474. American Society of Nephrology |
| ISSN: | 1046-6673 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|