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

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 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.

Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression

“…GP40-and GP84-knockout mice were more susceptible and resistant, respectively, to nondiabetic models of kidney fibrosis (45). Lepr db/db eNOS -/mice treated with a combined GP40 activator and GP84 inhibitor demonstrated improved mortality, renal histology, GFR, and glycemic control (31,45), similar to results we observed with FATP2 gene deletion. On the other hand, tubule-specific CD36-transgenic mice demonstrated no susceptibility to DKD, suggesting that downstream fatty acid channeling and metabolism may be transporter-specific (33).…”

“…Attenuated mortality in Slc27a2 -/-Lepr db/db eNOS -/mice. Lepr db/db eNOS -/mice on a C57BLKS/J genetic background have a reduced life span, and generally die before 26 weeks of age (12,31), though mean survival rates as long as 9 months have been described (26,32). Consistent with these reports, Figure 10 shows decreased survival in Slc27a2 +/+ Lepr db/db eNOS -/compared with WT and Slc27a2 +/+ Lepr db/db eNOS +/+ Figure 5.…”

“…In addition to faithfully mimicking progressive DKD (12,13), Slc27a2 +/+ Lepr db/db eNOS -/mice experience premature mortality, which is also an important hallmark of DKD in humans (55). The normal mouse life span is approximately 2 years, and mean survival rates of Slc27a2 +/+ Lepr db/db eNOS -/mice have ranged from 24 to 36 weeks (26,31,32), with 100% mortality as early as 26 weeks (31). These data are consistent with the 85% mortality we observed at 26 weeks.…”

Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators

“…For PBI-4050, a combined GPR84 antagonist and FFAR1 agonist, another FFA receptor targeting compound, was investigated for the treatment of IPF, with positive data acquired from an exploratory phase II study [ 196 ]. PBI-4050 treatment in preclinical models of diabetic nephropathy has also been shown to prevent kidneys from deteriorating function and fibrosis [ 197 ]. Another study could further show that PBI-4050 reduced renal damage in wild-type but not FFAR1 knock-out mice suffering from adenine-induced kidney injury, suggesting that therapeutic efficacy of this compound relies on the activation of FFAR1 rather than inhibition of GPR84 in this model [ 198 ].…”

Renal proximal tubule cell state and metabolism are coupled by nuclear receptors

“…Cellular metabolism, such as genes in lipid metabolism, fatty acid oxidation (FAO) and OX-PHOS showed strong correlation with disease state both in human and mouse CKD models (Chung et al, 2019;Kang et al, 2015). Pharmacological or genetic approaches that enhance FAO and mitochondrial biogenesis improved kidney function, however, the exact mechanism is not fully understood (Gomez et al, 2015;Lakhia et al, 2018;Li et al, 2018;Tran et al, 2011). Some studies indicate a key role of Nicotinamide adenine dinucleotide (NAD) donors in proximal tubule health and metabolism and suggest that improving mitochondrial function will lead to better NAD/NADH balance (Tran et al, 2016).…”