title: G-protein βγ subunit dimers modulate kidney repair after ischemia-reperfusion injury in rats.
abstract: Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein βγ subunit (Gβγ) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gβγ activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P < 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P < 0.05) the number of proliferating cell nuclear antigen-positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P < 0.05) S-phase cell cycle entry compared with vehicle-treated cells as determined by 5'-bromo-2'-deoxyuridine incorporation. Taken together, these data suggest that Gβγ signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury.
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: Sarah M
authors.initials: SM
authors.lastname: White
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: Lauren M
authors.initials: LM
authors.lastname: North
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: Emily
authors.initials: E
authors.lastname: Haines
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: Megan
authors.initials: M
authors.lastname: Goldberg
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Sullivan
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Pressly
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.).
authors.forename: David S
authors.initials: DS
authors.lastname: Weber
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.) kregner@mcw.edu fpark@uthsc.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Park
authors.affiliation: Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.) kregner@mcw.edu fpark@uthsc.edu.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Regner
mesh_terms: D000818:Animals; D059347:Cardio-Renal Syndrome / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D044387:GTP-Binding Protein beta Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D055503:Protein Multimerization; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D014966:Xanthenes; C007820:gallein