title: High-fat diet-induced renal cell apoptosis and oxidative stress in spontaneously hypertensive rat are ameliorated by fenofibrate through the PPARα-FoxO3a-PGC-1α pathway.
abstract: BACKGROUND
  The peroxisome proliferator-activated receptor-α (PPARα) is a lipid-sensing transcriptional factor that has a role in gluco-oxidative stress and lipotoxicity. Forkhead box O (FoxO)s and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α are also known to regulate cell metabolism, cell cycle arrest, apoptosis and oxidative stress during stressful conditions. We evaluated whether PPARα-FoxOs-PGC-1α signaling in overfed spontaneously hypertensive rats (SHR) has a protective role in the kidney.
  
  
  METHODS
  Male SHR and Wistar-Kyoto rats (WKY) fed a high-fat diet (HFD) received treatment with fenofibrate, PPARα agonist or tempol, antioxidants for 12 weeks and were evaluated about the PPARα-FoxOs-PGC-1α pathway.
  
  
  RESULTS
  The SHRs with an HFD had an elevated systolic pressure, plasma insulin, free fatty acid (FFA) and triglyceride (TGs) levels, and they had induced glucose intolerance as well as albuminuria, glomerular expansion and renal inflammation. An HFD caused the accumulation of intra-renal FFA and TGs and this was related to a decrease in the PPARα expression, the activation of phosphatidylinositol 3-kinase (PI3K)-Akt, phosphorylation of FoxO3a and decreases in the PGC-1α and estrogen-related receptor (ERR)-1α expressions, which suppressed the superoxide dismutase (SOD2) and Bcl-2 expressions and led to increases in oxidative stress and the number of apoptotic renal cells. Interestingly, administering fenofibrate or tempol to the HFD-induced SHRs reversed all of the renal phenotypes by increasing the PPARα expression with concomitant inactivation of the PI3K-Akt pathway, dephosphorylation of FoxO3a and activation of PGC-1α-ERR-1α signaling, and this all resulted in ameliorating the oxidative stress and apoptotic cell death.
  
  
  CONCLUSIONS
  Our results demonstrated that PPARα agonists or antioxidants are associated with improvement of the circulating FFA and TGs levels and this prevents HFD-induced renal lipotoxicity and hypertension by the activation of PPARα and its downstream signals of both FoxO3a and PGC-1α.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Hyun Wha
authors.initials: HW
authors.lastname: Chung
authors.forename: Ji Hee
authors.initials: JH
authors.lastname: Lim
authors.forename: Min Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Shin
authors.forename: Sungjin
authors.initials: S
authors.lastname: Chung
authors.forename: Bum Soon
authors.initials: BS
authors.lastname: Choi
authors.forename: Hyung Wook
authors.initials: HW
authors.lastname: Kim
authors.forename: Yong-Soo
authors.initials: YS
authors.lastname: Kim
authors.forename: Cheol Whee
authors.initials: CW
authors.lastname: Park
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Chang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D059305:Diet, High-Fat / Q000009:adverse effects*; D011345:Fenofibrate / Q000627:therapeutic use*; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007124:Immunoenzyme Techniques; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D011345:Fenofibrate