title: Epac-Rap signaling reduces cellular stress and ischemia-induced kidney failure.
abstract: Renal ischemia-reperfusion injury is associated with the loss of tubular epithelial cell-cell and cell-matrix interactions which contribute to renal failure. The Epac-Rap signaling pathway is a potent regulator of cell-cell and cell-matrix adhesion. The cyclic AMP analogue 8-pCPT-2'-O-Me-cAMP has been shown to selectively activate Epac, whereas the addition of an acetoxymethyl (AM) ester to 8-pCPT-2'-O-Me-cAMP enhanced in vitro cellular uptake. Here we demonstrate that pharmacological activation of Epac-Rap signaling using acetoxymethyl-8-pCPT-2'-O-Me-cAMP preserves cell adhesions during hypoxia in vitro, maintaining the barrier function of the epithelial monolayer. Intrarenal administration in vivo of 8-pCPT-2'-O-Me-cAMP also reduced renal failure in a mouse model for ischemia-reperfusion injury. This was accompanied by decreased expression of the tubular cell stress marker clusterin-α, and lateral expression of β-catenin after ischemia indicative of sustained tubular barrier function. Our study emphasizes the undervalued importance of maintaining tubular epithelial cell adhesion in renal ischemia and demonstrates the potential of pharmacological modulation of cell adhesion as a new therapeutic strategy to reduce the extent of injury in kidney disease and transplantation.
authors.affiliation: Division of Toxicology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Geurt
authors.initials: G
authors.lastname: Stokman
authors.forename: Yu
authors.initials: Y
authors.lastname: Qin
authors.forename: Hans-Gottfried
authors.initials: HG
authors.lastname: Genieser
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Bajema
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.forename: Leo S
authors.initials: LS
authors.lastname: Price
mesh_terms: D022005:Adherens Junctions / Q000502:physiology; D000818:Animals; D002448:Cell Adhesion; D015687:Cell Hypoxia; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D022001:Focal Adhesions; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D007511:Ischemia / Q000150:complications*; D007668:Kidney / Q000098:blood supply*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051437:Renal Insufficiency / Q000209:etiology*; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
chemical_list: C555650:8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate acetoxymethyl ester; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020827:rap1 GTP-Binding Proteins