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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

Sara M. Garrett, Ryan M. Whitaker, Craig C. Beeson and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics August 2014, 350 (2) 257-264; DOI: https://doi.org/10.1124/jpet.114.214700
Sara M. Garrett
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.)
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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 (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.)
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Craig C. Beeson
Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.)
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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 (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.)
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Abstract

Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1–100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone–uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase β, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1β subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator–activated receptor coactivator 1-α, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction.

Footnotes

    • Received March 17, 2014.
    • Accepted May 16, 2014.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM084147]; the National Institutes of Health National Center for Research Resources [Grant UL1-RR029882]; the Biomedical Laboratory Research and Development Program of the Department of Veterans Affairs [1BX000851]; the South Carolina Clinical and Translational Research Institute, with an academic home at the Medical University of South Carolina; and the National Institutes of Health Ruth L. Kirschstein National Research Service Award [Grant 5T32-DK083262-03]. Animal facilities were funded by the National Institutes of Health National Center for Research Resources [Grant C06-RR015455].

  • Portions of this work have been presented previously: Garrett SM, Wills LP, and Schnellmann RG (2012) Serotonin (5-HT) 1F receptor agonism as a potential treatment for acceleration of recovery from acute kidney injury. American Society of Nephrology Annual Meeting; 2012 Nov 1–4; San Diego, CA.

  • dx.doi.org/10.1124/jpet.114.214700.

  • U.S. Government work not protected by U.S. copyright
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Journal of Pharmacology and Experimental Therapeutics: 350 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 350, Issue 2
1 Aug 2014
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

5-HT1F Receptor Agonism Promotes Mitochondrial Biogenesis

Sara M. Garrett, Ryan M. Whitaker, Craig C. Beeson and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 257-264; DOI: https://doi.org/10.1124/jpet.114.214700

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

5-HT1F Receptor Agonism Promotes Mitochondrial Biogenesis

Sara M. Garrett, Ryan M. Whitaker, Craig C. Beeson and Rick G. Schnellmann
Journal of Pharmacology and Experimental Therapeutics August 1, 2014, 350 (2) 257-264; DOI: https://doi.org/10.1124/jpet.114.214700
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