FO008FATTY ACID RECEPTORS GPR40/GPR84: TWO PROMISING TARGETS IN KIDNEY FIBROSIS
Bibliographic record
Abstract
INTRODUCTION: Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors stimulated by free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although both receptors have been associated with metabolic regulation and inflammation, they have not been previously linked to organ fibrosis. The dual GPR40 agonist/GPR84 antagonist PBI-4050 (3-pentylbenzeneacetic acid sodium salt) is a novel antifibrotic drug candidate entering phase III in idiopathic pulmonary fibrosis (IPF) and Alström syndrome. The aim of this study was to determine the role of GPR40 and GPR84 receptors and the effect of PBI-4050 treatment in models of AKI and CKD. METHODS: PBI-4050 was tested in cells involved in fibrosis (macrophages, fibroblasts and epithelial cells) and in various animal models of CKD/DKD (5/6-nephrectomized rat, db/db and db/db eNOS-/- mice, adenine-induced CKD) and AKI (long-term postacute ischemic injury (IRI), LPS, unilateral ureteral obstruction (UUO), doxorubicin) and in GPR40- and GPR84-knockout mice. RESULTS: PBI-4050 acts on cells involved in the fibrotic pathway: macrophages, fibroblasts, and epithelial cells by regulating cytokines and fibrotic and remodeling markers. GPR40 is also expressed in proximal tubules and collecting duct while GPR84 is mainly expressed in podocytes. In experiments using either GPR40- or GPR84-knockout mice in models of kidney fibrosis (UUO, IRI, and adenine-induced CKD), GPR40 was found protective and GPR84 deleterious. Through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in other models of AKI (doxorubicin, LPS) and CKD/DKD (5/6-nephrectomy, db/db mice). Moreover, in two phase II clinical trials (type 2 diabetes with metabolic syndrome, Alström syndrome) involving a total of 36 patients, PBI-4050 reduced kidney injury urinary biomarkers. CONCLUSIONS: GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related kidney diseases.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".