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Research ArticleDrug Discovery and Translational Medicine

cGMP-Selective Phosphodiesterase Inhibitors Stimulate Mitochondrial Biogenesis and Promote Recovery from Acute Kidney Injury

Ryan M. Whitaker, Lauren P. Wills, L. Jay Stallons and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics December 2013, 347 (3) 626-634; DOI: https://doi.org/10.1124/jpet.113.208017
Ryan M. Whitaker
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
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Lauren P. Wills
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
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L. Jay Stallons
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
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Rick G. Schnellmann
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina; and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina
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Abstract

Recent studies demonstrate that mitochondrial dysfunction is a mediator of acute kidney injury (AKI). Consequently, restoration of mitochondrial function after AKI may be key to the recovery of renal function. Mitochondrial function can be restored through the generation of new, functional mitochondria in a process called mitochondrial biogenesis (MB). Despite its potential therapeutic significance, very few pharmacological agents have been identified to induce MB. To examine the efficacy of phosphodiesterase (PDE) inhibitors (PDE3: cAMP and cGMP activity; and PDE4: cAMP activity) in stimulating MB, primary cultures of renal proximal tubular cells (RPTCs) were treated with a panel of inhibitors for 24 hours. PDE3, but not PDE4, inhibitors increased the FCCP-uncoupled oxygen consumption rate (OCR), a marker of MB. Exposure of RPTCs to the PDE3 inhibitors, cilostamide and trequinsin, for 24 hours increased peroxisome proliferator–activated receptor γ coactivator-1α, and multiple mitochondrial electron transport chain genes. Cilostamide and trequinsin also increased mRNA expression of mitochondrial genes and mitochondrial DNA copy number in mice renal cortex. Consistent with these experiments, 8-Br-cGMP increased FCCP-uncoupled OCR and mitochondrial gene expression, whereas 8-Br-cAMP had no effect. The cGMP-specific PDE5 inhibitor sildenafil also induced MB in RPTCs and in vivo in mouse renal cortex. Treatment of mice with sildenafil after folic acid–induced AKI promoted restoration of MB and renal recovery. These data provide strong evidence that specific PDE inhibitors that increase cGMP are inducers of MB in vitro and in vivo, and suggest their potential efficacy in AKI and other diseases characterized by mitochondrial dysfunction and suppressed MB.

Footnotes

    • Received July 22, 2013.
    • Accepted September 16, 2013.
  • This study was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM084147 (to R.G.S.) and P20-GM103542-02 (to SC COBRE in Oxidants, Redox Balance, and Stress Signaling)]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants F30-DK096964 (to R.M.W.) and F32-DK098053 (to L.J.S.)]; the National Institutes of Health National Heart, Lung, and Blood Institute [Grant T32-HL007260]; the National Institutes of Health National Center for Research Resources [Grant C06-RR015455]; and the Department of Veterans Affairs Biomedical Laboratory Research and Development Program [Grant BX000851]. This publication was supported, in part, by the South Carolina Clinical and Translational Research Institute, with an academic home at the Medical University of South Carolina, and funded by the National Institutes of Health National Center for Research Resources [Grant UL1-RR029882].

  • This work was previously presented at the following meeting: Whitaker RM, Wills LP, and Schnellmann RG (2012) Phosphodiesterase inhibitors stimulate mitochondrial biogenesis: a potential therapy for AKI. American Society of Nephrology 2012 Kidney Week; 2012 October 30–November 4; San Diego, CA.

  • dx.doi.org/10.1124/jpet.113.208017.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 347 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 347, Issue 3
1 Dec 2013
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Research ArticleDrug Discovery and Translational Medicine

PDE Inhibitors Stimulate MB and Recovery from AKI

Ryan M. Whitaker, Lauren P. Wills, L. Jay Stallons and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 626-634; DOI: https://doi.org/10.1124/jpet.113.208017

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Research ArticleDrug Discovery and Translational Medicine

PDE Inhibitors Stimulate MB and Recovery from AKI

Ryan M. Whitaker, Lauren P. Wills, L. Jay Stallons and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics December 1, 2013, 347 (3) 626-634; DOI: https://doi.org/10.1124/jpet.113.208017
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