"Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control" published in JCI Insight
June 13th 2018
"Fatty acid receptor modulator PBI-4050 inhibits kidney fibrosis and improves glycemic control"
Yan Li,1,2,3 Sungjin Chung,1,2 Zhilian Li,1,2 Jessica M. Overstreet,1,2 Lyne Gagnon,4 Brigitte Grouix,4 Martin Leduc,4 Pierre Laurin,4 Ming-Zhi Zhang,1,2 and Raymond C. Harris1,2,5
JCI Insight. 2018;3(10):e120365. https://doi.org/10.1172/jci.insight.120365.
Copyright © 2018, American Society for Clinical Investigation
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.
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