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Molecular Pharmacology

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Research ArticleArticle

G-Protein βγ Subunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

Sarah M. White, Lauren M. North, Emily Haines, Megan Goldberg, Lydia M. Sullivan, Jeffrey D. Pressly, David S. Weber, Frank Park and Kevin R. Regner
Molecular Pharmacology October 2014, 86 (4) 369-377; DOI: https://doi.org/10.1124/mol.114.092346
Sarah M. White
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.)
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Lauren M. North
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.)
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Emily Haines
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.)
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Megan Goldberg
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.)
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Lydia M. Sullivan
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.)
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Jeffrey D. Pressly
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.)
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David S. Weber
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.)
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Frank Park
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.)
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Kevin R. Regner
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.)
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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.

Footnotes

    • Received February 21, 2014.
    • Accepted July 15, 2014.
  • S.M.W. and L.M.N. contributed equally to this work.

  • This work was funded by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK090123 (to F.P. and K.R.R.)] and with institutional funds provided by the University of Tennessee Health Sciences Center.

  • Part of this work was presented as a poster as follows: Haines EC, White SM, Park F, Regner KR (2012) Gβγ signaling plays a critical role in recovery from renal ischemia-reperfusion injury in rats. TH-PO088. American Society of Nephrology Kidney Week; 2012 Nov 1–4; San Diego, CA.

  • dx.doi.org/10.1124/mol.114.092346.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (4)
Molecular Pharmacology
Vol. 86, Issue 4
1 Oct 2014
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Research ArticleArticle

Role of Gβγ in Acute Kidney Injury

Sarah M. White, Lauren M. North, Emily Haines, Megan Goldberg, Lydia M. Sullivan, Jeffrey D. Pressly, David S. Weber, Frank Park and Kevin R. Regner
Molecular Pharmacology October 1, 2014, 86 (4) 369-377; DOI: https://doi.org/10.1124/mol.114.092346

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Research ArticleArticle

Role of Gβγ in Acute Kidney Injury

Sarah M. White, Lauren M. North, Emily Haines, Megan Goldberg, Lydia M. Sullivan, Jeffrey D. Pressly, David S. Weber, Frank Park and Kevin R. Regner
Molecular Pharmacology October 1, 2014, 86 (4) 369-377; DOI: https://doi.org/10.1124/mol.114.092346
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