Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control

• Published in: JCI insight 2018-05, Vol.3 (10)
• Main Authors: Li, Yan, Chung, Sungjin, Li, Zhilian, Overstreet, Jessica M, Gagnon, Lyne, Grouix, Brigitte, Leduc, Martin, Laurin, Pierre, Zhang, Ming-Zhi, Harris, Raymond C
• Format: Article
• Language: English
• Subjects: Acetates - pharmacology; Acetates - therapeutic use; Animals; Blood Glucose - metabolism; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - metabolism; Disease Models, Animal; Fatty Acids - metabolism; Fibrosis; Kidney - pathology; Membrane Proteins - metabolism; Mice; Receptors, Cell Surface - drug effects; Receptors, Cell Surface - metabolism
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.120365

Extensive kidney fibrosis occurs in several types of chronic kidney diseases. PBI-4050, a potentially novel first-in-class orally active low-molecular weight compound, has antifibrotic and antiinflammatory properties. We examined whether PBI-4050 affected the progression of diabetic nephropathy (DN) in a mouse model of accelerated type 2 diabetes and in a model of selective tubulointerstitial fibrosis. eNOS-/- db/db mice were treated with PBI-4050 from 8-20 weeks of age (early treatment) or from 16-24 weeks of age (late treatment). PBI-4050 treatment ameliorated the fasting hyperglycemia and abnormal glucose tolerance tests seen in vehicle-treated mice. In addition, PBI-4050 preserved (early treatment) or restored (late treatment) blood insulin levels and increased autophagy in islets. PBI-4050 treatment led to significant improvements in lifespan in the diabetic mice. Both early and late PBI-4050 treatment protected against progression of DN, as indicated by reduced histological glomerular injury and albuminuria, slow decline of glomerular filtration rate, and loss of podocytes. PBI-4050 inhibited kidney macrophage infiltration, oxidative stress, and TGF-β-mediated fibrotic signaling pathways, and it also protected against the development of tubulointerstitial fibrosis. To confirm a direct antiinflammatory/antifibrotic effect in the kidney, further studies with a nondiabetic model of EGFR-mediated proximal tubule activation confirmed that PBI-4050 dramatically decreased the development of the associated tubulointerstitial injury and macrophage infiltration. These studies suggest that PBI-4050 attenuates development of DN in type 2 diabetes through improvement of glycemic control and inhibition of renal TGF-β-mediated fibrotic pathways, in association with decreases in macrophage infiltration and oxidative stress.