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

Abstract

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.

Extracellular Vesicles: Cell-Derived Biomarkers of Glomerular and Tubular Injury

“…PBI-4050 is an agonist of the G protein-coupled receptor 40 that has been consistently shown to reduce kidney fibrosis and inflammation in preclinical models [29,30]. We observed that PBI-4050 treatment was associated with lower levels of tubular lEVs parallel to improvement in tubular injury in adenine-fed mice [30]. Thus tubular lEVs appeared to be indicative of response to therapy in this animal model.…”

“…We recently studied proximal tubulederived lEVs (megalin + ) in a mouse model of adenine-CKD treated with PBI-4050. PBI-4050 is an agonist of the G protein-coupled receptor 40 that has been consistently shown to reduce kidney fibrosis and inflammation in preclinical models [29,30]. We observed that PBI-4050 treatment was associated with lower levels of tubular lEVs parallel to improvement in tubular injury in adenine-fed mice [30].…”

Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

“…After 6 weeks of adenine-enriched diet, a significant decrease of renal XDH expression took place in WT and AhR −/− mice reflecting cell death. Indeed, renal apoptosis and adenine-induced PT-cell apoptosis were demonstrated in other mouse models of prolonged administration of an adenine diet [50,51]. XDH can be induced by tetrachlorodibenzo-p-dioxin, a well-known AhR agonist [52].…”

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“…All mice from this group exhibited body weight loss that we can explain by the low palatability of adenine diet for mice and consequently a reduced food intake as described in numerous recent studies. [19][20][21] A high adenine diet (ranging 0.2% to 0.3%) is known to induce CKD in mice via the development of tubulointerstitial nephropathy, [22][23][24] whereas 5/6Nx is regarded as a model of nephron reduction followed by glomerulosclerosis due to hyperfiltration injury. 25 In our study, kidney histology and PCR analysis are in accordance with the literature with an increase in renal inflammation and fibrosis in adenine-fed mice and increased glomerular collagen deposition in the remnant kidney of 5/6Nx mice.…”