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Mol Pharmacol. 2014 Oct;86(4):369-77. doi: 10.1124/mol.114.092346. Epub 2014 Jul 15.

G-protein βγ subunit dimers modulate kidney repair after ischemia-reperfusion injury in rats.

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  • 1Department 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.).
  • 2Department 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.

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.

Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

PMID:
25028481
[PubMed - indexed for MEDLINE]
PMCID:
PMC4164983
[Available on 2015-10-01]
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