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A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice.
Wang, Xiaoxin X; Luo, Yuhuan; Wang, Dong; Adorini, Luciano; Pruzanski, Mark; Dobrinskikh, Evgenia; Levi, Moshe.
Afiliação
  • Wang XX; From the Division of Renal Diseases and Hypertension, Department of Medicine, Denver Veterans Affairs Medical Center and University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045 and.
  • Luo Y; From the Division of Renal Diseases and Hypertension, Department of Medicine, Denver Veterans Affairs Medical Center and University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045 and.
  • Wang D; From the Division of Renal Diseases and Hypertension, Department of Medicine, Denver Veterans Affairs Medical Center and University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045 and.
  • Adorini L; Intercept Pharmaceuticals, New York, New York 10001.
  • Pruzanski M; Intercept Pharmaceuticals, New York, New York 10001.
  • Dobrinskikh E; From the Division of Renal Diseases and Hypertension, Department of Medicine, Denver Veterans Affairs Medical Center and University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045 and.
  • Levi M; From the Division of Renal Diseases and Hypertension, Department of Medicine, Denver Veterans Affairs Medical Center and University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045 and Moshe.Levi@ucdenver.edu.
J Biol Chem ; 292(29): 12018-12024, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28596381
ABSTRACT
Even in healthy individuals, renal function gradually declines during aging. However, an observed variation in the rate of this decline has raised the possibility of slowing or delaying age-related kidney disease. One of the most successful interventional measures that slows down and delays age-related kidney disease is caloric restriction. We undertook the present studies to search for potential factors that are regulated by caloric restriction and act as caloric restriction mimetics. Based on our prior studies with the bile acid-activated nuclear hormone receptor farnesoid X receptor (FXR) and G protein-coupled membrane receptor TGR5 that demonstrated beneficial effects of FXR and TGR5 activation in the kidney, we reasoned that FXR and TGR5 could be excellent candidates. We therefore determined the effects of aging and caloric restriction on the expression of FXR and TGR5 in the kidney. We found that FXR and TGR5 expression levels are decreased in the aging kidney and that caloric restriction prevents these age-related decreases. Interestingly, in long-lived Ames dwarf mice, renal FXR and TGR5 expression levels were also increased. A 2-month treatment of 22-month-old C57BL/6J mice with the FXR-TGR5 dual agonist INT-767 induced caloric restriction-like effects and reversed age-related increases in proteinuria, podocyte injury, fibronectin accumulation, TGF-ß expression, and, most notably, age-related impairments in mitochondrial biogenesis and mitochondrial function. Furthermore, in podocytes cultured in serum obtained from old mice, INT-767 prevented the increases in the proinflammatory markers TNF-α, toll-like receptor 2 (TLR2), and TLR4. In summary, our results indicate that FXR and TGR5 may play an important role in modulation of age-related kidney disease.
Assuntos
Texto completo: Disponível Coleções: Bases de dados internacionais Contexto em Saúde: Agenda de Saúde Sustentável para as Américas Tema em saúde: Objetivo 9: Redução de doenças não transmissíveis Base de dados: MEDLINE Assunto principal: Envelhecimento / Ácidos e Sais Biliares / Anti-Inflamatórios não Esteroides / Receptores Citoplasmáticos e Nucleares / Receptores Acoplados a Proteínas-G / Insuficiência Renal / Rim Idioma: Inglês Revista: J Biol Chem Ano de publicação: 2017 Tipo de documento: Artigo

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Texto completo: Disponível Coleções: Bases de dados internacionais Contexto em Saúde: Agenda de Saúde Sustentável para as Américas Tema em saúde: Objetivo 9: Redução de doenças não transmissíveis Base de dados: MEDLINE Assunto principal: Envelhecimento / Ácidos e Sais Biliares / Anti-Inflamatórios não Esteroides / Receptores Citoplasmáticos e Nucleares / Receptores Acoplados a Proteínas-G / Insuficiência Renal / Rim Idioma: Inglês Revista: J Biol Chem Ano de publicação: 2017 Tipo de documento: Artigo