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

JCI Insight
Yan LiRaymond C Harris

Abstract

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...Continue Reading

References

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Citations

Jul 17, 2019·Clinical Science·Jean-François ThibodeauLyne Gagnon
Oct 22, 2019·Endocrine Reviews·Yuliya LytvynDavid Z I Cherney
Sep 2, 2020·British Journal of Pharmacology·Sara MarsangoGraeme Milligan
Feb 14, 2021·International Journal of Molecular Sciences·Manuel GrundmannFrank Eitner
Feb 6, 2020·Trends in Pharmacological Sciences·Andrew J HaakDaniel J Tschumperlin
Apr 17, 2021·Frontiers in Medicine·Jingsheng ChangYifei Zhong
May 14, 2021·Transplantation·Turgay Saritas, Rafael Kramann
Oct 27, 2020·Mini Reviews in Medicinal Chemistry·Lata RaniSukhbir Singh

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