Abstract
Neural vascular insufficiency plays an important role in diabetic peripheral neuropathy (DPN). Peroxisome proliferative-activated receptor (PPAR)α has an endothelial protective effect related to activation of PPARγ coactivator (PGC)-1α and vascular endothelial growth factor (VEGF), but its role in DPN is unknown. We investigated whether fenofibrate would improve DPN associated with endothelial survival through AMPK-PGC-1α-eNOS pathway. Fenofibrate was given to db/db mice in combination with anti-flt-1 hexamer and anti-flk-1 heptamer (VEGFR inhibition) for 12 weeks. The db/db mice displayed sensory-motor impairment, nerve fibrosis and inflammation, increased apoptotic cells, disorganized myelin with axonal shrinkage and degeneration, fewer unmyelinated fibers, and endoneural vascular rarefaction in the sciatic nerve compared to db/m mice. These findings were exacerbated with VEGFR inhibition in db/db mice. Increased apoptotic cell death and endothelial dysfunction via inactivation of the PPARα-AMPK-PGC-1α pathway and their downstream PI3K-Akt-eNOS-NO pathway were noted in db/db mice, human umbilical vein endothelial cells (HUVECs) and human Schwann cells (HSCs) in high-glucose media. The effects were more prominent in response to VEGFR inhibition. In contrast, fenofibrate treatment ameliorated neural and endothelial damage by activating the PPARα-AMPK-PGC-1α-eNOS pathway in db/db mice, HUVECs and HSCs. Fenofibrate could be a promising therapy to prevent DPN by protecting endothelial cells through VEGF-independent activation of the PPARα-AMPK-PGC-1α-eNOS-NO pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Hydroxy-2'-Deoxyguanosine
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AMP-Activated Protein Kinases / metabolism
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Adenosine Monophosphate / metabolism
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Animals
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Blood Glucose
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Body Weight
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Cell Survival / drug effects
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Deoxyguanosine / analogs & derivatives
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Deoxyguanosine / metabolism
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Diabetic Neuropathies / drug therapy
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Diabetic Neuropathies / metabolism*
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Diabetic Neuropathies / physiopathology
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Disease Models, Animal
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Endothelial Cells / drug effects*
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Endothelial Cells / metabolism*
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Fenofibrate / administration & dosage
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Fenofibrate / pharmacology*
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Fibrosis
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Glycated Hemoglobin / metabolism
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Human Umbilical Vein Endothelial Cells / drug effects
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Lipids / blood
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Mice
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Neural Conduction / drug effects
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PPAR alpha / metabolism
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
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Schwann Cells / drug effects
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Schwann Cells / metabolism
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Sciatic Nerve / drug effects
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Sciatic Nerve / metabolism
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Sciatic Nerve / pathology
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Sciatic Nerve / physiopathology
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Sciatic Neuropathy / drug therapy
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Sciatic Neuropathy / metabolism
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Sciatic Neuropathy / physiopathology
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Transcription Factors / metabolism
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Transforming Growth Factor beta1 / metabolism
Substances
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Blood Glucose
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Glycated Hemoglobin A
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lipids
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PPAR alpha
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Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
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Platelet Endothelial Cell Adhesion Molecule-1
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Ppargc1a protein, mouse
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Transcription Factors
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Transforming Growth Factor beta1
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Adenosine Monophosphate
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8-Hydroxy-2'-Deoxyguanosine
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Receptors, Vascular Endothelial Growth Factor
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AMP-Activated Protein Kinases
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Deoxyguanosine
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Fenofibrate
Grants and funding
This study was supported by grants of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (C.W.P; A111055) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (H.W.K; 2012R1A1A3020151). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.