PBI-4050 via GPR40 activation improves adenine-induced kidney injury in mice

PBI-4050, a novel first-in-class orally active compound that has completed clinical phases Ib and II in subjects with CKD and metabolic syndrome respectively, exerts antifibrotic effects in several organs via a novel mechanism of action, partly through activation of the 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 pathway. Adenine-induced CKD was achieved in eight-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 three 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 levels. Adenine-induced renal fibrosis, 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 to 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 an...

Source: Clinical Science - July 14, 2019 Category: Biomedical Science Authors: Thibodeau, J.-F., Simard, J.-C., Holterman, C. E., Blais, A., Cloutier, M.-P., Medeiros, T., Leduc, M., Grouix, B., Leblond, F. A., Burger, D., Hebert, R. L., Kennedy, C. R. J., Gagnon, L. Tags: PublishAheadOfPrint Source Type: research