title: Inhibition of Ras/ERK1/2 signaling protects against postischemic renal injury.
abstract: The small GTPase p21 Ras and its downstream effectors play a central role in the control of cell survival and apoptosis. We studied the effects of Ras/ERK1/2 signaling inhibition on oxidative damage in cultured renal and endothelial cells and on renal ischemia-reperfusion injury in the rat. Primary human renal tubular and human endothelial ECV304 cells underwent significant cell death when subjected to oxidative stress. This type of stress induced robustly ERK1/2 and phosphoinositide 3-kinase (PI3-kinase) signaling. Inhibition of Ras/ERK1/2 with a farnesyl transferase inhibitor, chaetomellic acid A (S-FTI), or with PD-98059, an inhibitor of MEK, a kinase upstream ERK1/2, significantly reduced the fraction of dead cells. The inhibitor of the PI3-kinase/Akt pathway, LY-294002, failed to exert a protective effect. We have translated these data in a rat model of renal ischemic injury in vivo. In uninephrectomized animals, anesthetized with pentobarbital sodium (Nembutal, 50 mg/kg i.p.), 24 h after an acute ischemic renal insult (45-min occlusion of left renal artery) a significant fraction of kidney cells succumbed to cell death resulting in renal failure [glomerular filtration rate (GFR) 0.17 +/- 0.1 vs. 0.90 +/- 0.4 ml x min(-1) x 100 g body wt(-1) in normal rats]. Rats treated with S-FTI maintained the renal function (GFR 0.50 +/- 0.1 ml x min(-1) x 100 g body wt(-1)), and the kidneys showed a significant reduction of tubular necrosis. Reduction of ischemic damage in kidney and tubular cells paralleled Ha-Ras inhibition, assayed by cytosolic translocation of the protein. These data demonstrate that inhibition of farnesylation and consequently of Ras/ERK1/2 signaling significantly reduces acute postischemic renal injury.
authors.affiliation: University Magna Graecia of Catanzaro, Italy sabbatin@unina.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Sabbatini
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Santillo
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.forename: Roberto
authors.initials: R
authors.lastname: Paternò
authors.forename: Francesco
authors.initials: F
authors.lastname: Uccello
authors.forename: Rosalba
authors.initials: R
authors.lastname: Serù
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Matrone
authors.forename: Gianrico
authors.initials: G
authors.lastname: Spagnuolo
authors.forename: Michele
authors.initials: M
authors.lastname: Andreucci
authors.forename: Vittorio
authors.initials: V
authors.lastname: Serio
authors.forename: Pasquale
authors.initials: P
authors.lastname: Esposito
authors.forename: Bruno
authors.initials: B
authors.lastname: Cianciaruso
authors.forename: Giorgio
authors.initials: G
authors.lastname: Fuiano
authors.forename: Enrico V
authors.initials: EV
authors.lastname: Avvedimento
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D007668:Kidney / Q000098:blood supply*; D007684:Kidney Tubules; D008297:Male; D008298:Maleates / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D014471:Umbilical Veins
chemical_list: D008298:Maleates; C080569:chaetomellic acid A; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016283:Proto-Oncogene Proteins p21(ras)