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PBI-4050 via GPR40 activation improves adenine-induced kidney injury in mice.
Thibodeau, Jean-François; Simard, Jean-Christophe; Holterman, Chet E; Blais, Amélie; Cloutier, Marie-Pier; Medeiros, Thalia; Leduc, Martin; Grouix, Brigitte; Leblond, François A; Burger, Dylan; Hébert, Richard L; Kennedy, Christopher R J; Gagnon, Lyne.
Afiliación
  • Thibodeau JF; Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada j.thibodeau@prometic.com.
  • Simard JC; Prometic Biosciences Inc., Laval, QC, Canada.
  • Holterman CE; Prometic Biosciences Inc., Laval, QC, Canada.
  • Blais A; Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Cloutier MP; Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Medeiros T; Prometic Biosciences Inc., Laval, QC, Canada.
  • Leduc M; Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Grouix B; Prometic Biosciences Inc., Laval, QC, Canada.
  • Leblond FA; Prometic Biosciences Inc., Laval, QC, Canada.
  • Burger D; Prometic Biosciences Inc., Laval, QC, Canada.
  • Hébert RL; Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
  • Kennedy CRJ; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
  • Gagnon L; Kidney Research Center, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
Clin Sci (Lond) ; 133(14): 1587-1602, 2019 07 31.
Article en En | MEDLINE | ID: mdl-31308217
PBI-4050 (3-pentylbenzenacetic acid sodium salt), a novel first-in-class orally active compound that has completed clinical Phases Ib and II in subjects with chronic kidney disease (CKD) and metabolic syndrome respectively, exerts antifibrotic effects in several organs via a novel mechanism of action, partly through activation of the G protein receptor 40 (GPR40) receptor. Here we evaluate the effects of PBI-4050 in both WT and Gpr40-/- mice on adenine-induced tubulointerstitial injury, anemia and activation of the unfolded protein response (UPR) pathway. Adenine-induced CKD was achieved in 8-week-old C57BL/6 mice fed a diet supplemented with 0.25% adenine. After 1 week, PBI-4050 or vehicle was administered daily by oral-gavage for 3 weeks. Gpr40-/- mice were also subjected to adenine-feeding, with or without PBI-4050 treatment. PBI-4050 improved renal function and urine concentrating ability. Anemia was present in adenine-fed mice, while PBI-4050 blunted these effects and led to significantly higher plasma erythropoietin (EPO) levels. Adenine-induced renal fibrosis, endoplasmic reticulum (ER) stress and apoptosis were significantly decreased by PBI-4050. In parallel, Gpr40-/- mice were more susceptible to adenine-induced fibrosis, renal function impairment, anemia and ER stress compared with WT mice. Importantly, PBI-4050 treatment in Gpr40-/- mice failed to reduce renal injury in this model. Taken together, PBI-4050 prevented adenine-induced renal injury while these beneficial effects were lost upon Gpr40 deletion. These data reinforce PBI-4050's use as a renoprotective therapy and identify GPR40 as a crucial mediator of its beneficial effects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenina / Receptores Acoplados a Proteínas G / Riñón / Enfermedades Renales / Acetatos Tipo de estudio: Etiology_studies Límite: Animals / Humans / Male Idioma: En Revista: Clin Sci (Lond) Año: 2019 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Adenina / Receptores Acoplados a Proteínas G / Riñón / Enfermedades Renales / Acetatos Tipo de estudio: Etiology_studies Límite: Animals / Humans / Male Idioma: En Revista: Clin Sci (Lond) Año: 2019 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Reino Unido