title: Caloric restriction ameliorates kidney ischaemia/reperfusion injury through PGC-1α-eNOS pathway and enhanced autophagy.
abstract: OBJECTIVE
  We investigated whether preconditioning with caloric restriction (CR) ameliorates kidney ischaemia/reperfusion (I/R) injury and whether the salutary effects of CR are mediated through enhanced autophagy and/or activation of key metabolic sensors SIRT1, AMP-kinase and PGC-1α.
  
  
  METHODS
  Six- to seven-week-old Wistar rats were divided into three groups: (i) sham-operated group; (ii) I/R group (40-min ischaemia followed by 24 h of reperfusion); and (iii) I/R group kept under CR (energy intake 70%) for 2 weeks before surgery. In additional experiments, sirtinol and 3-methyladenine (3-MA) were used as inhibitors of SIRT1 and autophagy respectively. Renal function was measured, and acute tubular damage and nitrotyrosine expression were scored. Kidney adenosine monophosphate-activated kinase (AMPK), SIRT1, eNOS, PGC-1α and LC-3B expressions were measured.
  
  
  RESULTS
  Caloric restriction improved renal function, protected against the development of acute tubular necrosis and attenuated I/R-induced nitrosative stress. Kidney I/R injury decreased eNOS and PGC-1α expression, inhibit autophagy and increased SIRT1 and AMPK expressions by 2.6- and fourfold respectively. However, phosphorylation level of AMPK was decreased. As compared with I/R injury group, CR further increased kidney SIRT1 expression by 1.8-fold, promoted autophagy and counteracted I/R-induced decreases in the expression of eNOS and PGC-1α. 3-MA abolished the renoprotective effects of CR, whereas sirtinol did not influence renal function in CR rats with I/R injury.
  
  
  CONCLUSIONS
  Caloric restriction ameliorates acute kidney I/R injury through enhanced autophagy and counteraction of I/R-induced decreases in the renal expression of eNOS and PGC-1α.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Lempiäinen
authors.forename: P
authors.initials: P
authors.lastname: Finckenberg
authors.forename: E E
authors.initials: EE
authors.lastname: Mervaala
authors.forename: S
authors.initials: S
authors.lastname: Sankari
authors.forename: J
authors.initials: J
authors.lastname: Levijoki
authors.forename: E M
authors.initials: EM
authors.lastname: Mervaala
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology; D031204:Caloric Restriction; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D007249:Inflammation / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000473:pathology / Q000502:physiology; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D013312:Stress, Physiological; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: PGC-1α; SIRT1; autophagy; caloric restriction; eNOS; ischaemia/reperfusion injury