SP345ACTIVATION OF THE FREE-FATTY ACID RECEPTOR GPR40 IMPROVES ANEMIA IN MOUSE MODELS OF KIDNEY DISEASE VIA A NOVEL EPO-INDEPENDENT MECHANISM OF ACTION
Bibliographic record
Abstract
INTRODUCTION: The prevalence of anemia increases with the progression of chronic kidney disease (CKD) and leads to reduced quality of life and increased cardiovascular risk. Yet, the use of erythropoiesis stimulating agents is associated with negative outcomes in CKD patients. Here we present an alternative pathway for the treatment of anemia secondary to kidney disease through activation of GPR40, in mediating in vitro stimulation of bone marrow cells, particularly the colony-forming-unit-erythrocytes (CFU-E) generation; and the anti-anemic effects of PBI-4050 in models of renal injury. METHODS:In vitro, murine bone marrow cells were assayed for CFU-E in the presence or absence of PBI-4050 (agonist of GPR40) and/or GW1100 (GPR40 antagonist). PBI-4050 was tested in ischemia-reperfusion (IR) AKI in WT mice. In addition, we used an adenine-induced CKD model whereby male wild type (WT) and GPR40-/- mice were fed a diet supplemented with 0.25% adenine for one week and treated for three weeks with PBI-4050 (200 mg/kg). RESULTS: PBI-4050 increased the formation of CFU-E in a GPR40 dependent manner as GW1100 blocked this increase. In addition, GPR40 antagonism led to a significant decrease in CFU-E counts. Furthermore, PBI-4050 showed comparable activity to EPO regarding CFU-E count. After 14 days following IR-AKI, PBI-4050 maintained hematocrit. In adenine-CKD mice, Hct, Hb and mean corpuscular volume were significantly decreased in CKD-mice, while PBI-4050 maintained these levels and led to significantly higher plasma erythropoietin levels. In parallel, signs of anemia were present to similar degrees in both untreated WT and GPR40-/- mice. Interestingly, PBI-4050 treatment in adenine-fed GPR40-/- mice failed to improve Hct levels. CONCLUSIONS: Taken together, our data suggest treatment of anemia through a novel alternative pathway which is EPO-independent. Treatment with PBI-4050 may provide therapeutic benefit by maintaining adequate Hct and Hb levels, while also improving renal and cardiovascular outcomes.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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".