PMID- 24392081 OWN - NLM STAT- MEDLINE DCOM- 20141118 LR - 20221207 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 1 DP - 2014 TI - Therapeutic effects of fenofibrate on diabetic peripheral neuropathy by improving endothelial and neural survival in db/db mice. PG - e83204 LID - 10.1371/journal.pone.0083204 [doi] LID - e83204 AB - Neural vascular insufficiency plays an important role in diabetic peripheral neuropathy (DPN). Peroxisome proliferative-activated receptor (PPAR)alpha has an endothelial protective effect related to activation of PPARgamma coactivator (PGC)-1alpha 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-1alpha-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 PPARalpha-AMPK-PGC-1alpha 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 PPARalpha-AMPK-PGC-1alpha-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 PPARalpha-AMPK-PGC-1alpha-eNOS-NO pathway. FAU - Cho, Ye Rim AU - Cho YR AD - Rehabilitation Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Lim, Ji Hee AU - Lim JH AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Kim, Min Young AU - Kim MY AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Kim, Tae Woo AU - Kim TW AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Hong, Bo Young AU - Hong BY AD - Rehabilitation Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Kim, Yong-Soo AU - Kim YS AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Chang, Yoon Sik AU - Chang YS AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Kim, Hye Won AU - Kim HW AD - Rehabilitation Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. FAU - Park, Cheol Whee AU - Park CW AD - Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140102 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Blood Glucose) RN - 0 (Glycated Hemoglobin A) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Lipids) RN - 0 (PPAR alpha) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Platelet Endothelial Cell Adhesion Molecule-1) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Transcription Factors) RN - 0 (Transforming Growth Factor beta1) RN - 415SHH325A (Adenosine Monophosphate) RN - 88847-89-6 (8-Hydroxy-2'-Deoxyguanosine) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - G9481N71RO (Deoxyguanosine) RN - U202363UOS (Fenofibrate) SB - IM MH - 8-Hydroxy-2'-Deoxyguanosine MH - AMP-Activated Protein Kinases/metabolism MH - Adenosine Monophosphate/metabolism MH - Animals MH - Blood Glucose MH - Body Weight MH - Cell Survival/drug effects MH - Deoxyguanosine/analogs & derivatives/metabolism MH - Diabetic Neuropathies/drug therapy/*metabolism/physiopathology MH - Disease Models, Animal MH - Endothelial Cells/*drug effects/*metabolism MH - Fenofibrate/administration & dosage/*pharmacology MH - Fibrosis MH - Glycated Hemoglobin/metabolism MH - Human Umbilical Vein Endothelial Cells/drug effects/metabolism MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Lipids/blood MH - Mice MH - Neural Conduction/drug effects MH - PPAR alpha/metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MH - Platelet Endothelial Cell Adhesion Molecule-1/metabolism MH - Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors MH - Schwann Cells/drug effects/metabolism MH - Sciatic Nerve/drug effects/metabolism/pathology/physiopathology MH - Sciatic Neuropathy/drug therapy/metabolism/physiopathology MH - Transcription Factors/metabolism MH - Transforming Growth Factor beta1/metabolism PMC - PMC3879243 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2014/01/07 06:00 MHDA- 2014/11/19 06:00 PMCR- 2014/01/02 CRDT- 2014/01/07 06:00 PHST- 2013/05/27 00:00 [received] PHST- 2013/10/31 00:00 [accepted] PHST- 2014/01/07 06:00 [entrez] PHST- 2014/01/07 06:00 [pubmed] PHST- 2014/11/19 06:00 [medline] PHST- 2014/01/02 00:00 [pmc-release] AID - PONE-D-13-21540 [pii] AID - 10.1371/journal.pone.0083204 [doi] PST - epublish SO - PLoS One. 2014 Jan 2;9(1):e83204. doi: 10.1371/journal.pone.0083204. eCollection 2014.