title: Caloric Restriction Is More Efficient than Physical Exercise to Protect from Cisplatin Nephrotoxicity via PPAR-Alpha Activation.
abstract: The antineoplastic drug cisplatin promotes renal injury, which limits its use. Protocols that reduce renal cisplatin toxicity will allow higher doses to be used in cisplatin treatment. Here, we compare physical exercise and caloric restriction (CR) as protocols to reduce cisplatin renal injury in mice. Male C57BL/6 were divided into four groups: Control, cisplatin, exercise + cisplatin, and 30% CR + cisplatin. Animals were injected with a single dose of cisplatin (20 mg/kg i.p.) and sacrificed 96 h after injection. Quantitative real time PCR, histological analyses, immunohistochemistry, and biochemical measurements were performed to investigate renal injury, necrosis, apoptosis, and inflammatory mechanisms. Both protocols protected against cisplatin renal injury, but CR was more effective in reducing uraemia and renal necrosis. The CR + Cisplatin group exhibited reduced serum IL-1β and TNF-α levels. No differences were noted in the renal mRNA expression of cytokines. Both interventions reduced apoptosis, but only the CR + Cisplatin group decreased TNFR2 protein expression. PPAR-α was activated in mice after CR. An antagonist of PPAR-α blocked the protective effect of CR. Both interventions attenuated the nephrotoxicity caused by cisplatin injection, but CR + Cisplatin showed a better response by modulating TNFR2. Moreover, part of the CR benefit depends on PPAR-α activation.
authors.affiliation: Departamento de Biofísica, Universidade Federal de São PauloSão Paulo, Brazil; Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São PauloSão Paulo, Brazil.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Estrela
authors.affiliation: Departamento de Biofísica, Universidade Federal de São PauloSão Paulo, Brazil; Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São PauloSão Paulo, Brazil.
authors.forename: Frederick
authors.initials: F
authors.lastname: Wasinski
authors.affiliation: Departamento de Biofísica, Universidade Federal de São PauloSão Paulo, Brazil; Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São PauloSão Paulo, Brazil.
authors.forename: Rogério O
authors.initials: RO
authors.lastname: Batista
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo São Paulo, Brazil.
authors.forename: Meire I
authors.initials: MI
authors.lastname: Hiyane
authors.affiliation: Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo São Paulo, Brazil.
authors.forename: Raphael J F
authors.initials: RJ
authors.lastname: Felizardo
authors.affiliation: Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo São Paulo, Brazil.
authors.forename: Flavia
authors.initials: F
authors.lastname: Cunha
authors.affiliation: Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo São Paulo, Brazil.
authors.forename: Danilo C
authors.initials: DC
authors.lastname: de Almeida
authors.affiliation: Departamento de Clinica Médica, Universidade de São Paulo São Paulo, Brazil.
authors.forename: Denise M A C
authors.initials: DM
authors.lastname: Malheiros
authors.affiliation: Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo São Paulo, Brazil.
authors.forename: Niels O S
authors.initials: NO
authors.lastname: Câmara
authors.affiliation: Departamento de Nutrição, Escola de Nutrição, Universidade Federal de Pelotas Pelotas, Brazil.
authors.forename: Carlos C
authors.initials: CC
authors.lastname: Barros
authors.affiliation: Max-Delbruck Center for Molecular Medicine Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.affiliation: Departamento de Biofísica, Universidade Federal de São Paulo São Paulo, Brazil.
authors.forename: Ronaldo C
authors.initials: RC
authors.lastname: Araujo
keywords: PPAR-alpha; caloric restriction; cisplatin nephrotoxicity; exercise; inflammation