FP266PBI-4050 REDUCES SYSTEMIC INFLAMMATION, ELECTROLYTE DISTURBANCES, AND RENAL INJURY IN MICE WITH SEPSIS-INDUCED ACUTE KIDNEY INJURY; ROLE OF GPR84
Bibliographic record
Abstract
INTRODUCTION: PBI-4050, a dual GPR40 agonist/GPR84 antagonist, exerts anti-inflammatory and antifibrotic effects in several diabetic and non-diabetic models of kidney injury. Primarily in macrophages and fibroblasts, we have shown that the pro-inflammatory GPR84 receptor is induced in cultured human renal cells including proximal tubule epithelial cells (hPTEC) and podocytes (hPod) stimulated with bacterial lipopolysaccharides (LPS). We therefore queried the impact of PBI-4050 in a model of endotoxemia-induced AKI and evaluated the role of GPR84 in this regard. METHODS: Eight-week old male C57BL/6 mice were treated with PBI-4050 (200 mg/kg BW, p.o.) for 14 days, followed by LPS (10 mg/kg, i.p.)-challenge and sacrificed 24 hours later. RESULTS: AKI was confirmed as LPS led to a rapid rise in plasma creatinine and urea, which were significantly decreased in PBI-4050-treated mice. LPS-induced hyperphosphatemia, hyperkalemia, hypocalcaemia and hypoglycemia, were also significantly improved by PBI-4050. Circulating levels of several major pro-inflammatory cytokines, including IL-1β, IL-6, MCP-1, TNFα, CXCL-1 and Rantes (CCL5) correlated with creatinine levels, and were significantly decreased by PBI-4050 in LPS mice. Moreover, PBI-4050 reduced LPS-induced albuminuria and albuminemia. Histological assessment revealed tubular cell injury was reduced and PT-megalin expression improved with PBI-4050, as was peri-glomerular and tubulointerstitial α-SMA expression. In a pilot study, GPR84-/- mice challenged with 24 hours LPS showed modest yet significant improvements in renal function. LPS caused GPR84 induction in cultured hPTECs and hPODs. PBI-4050 treatment in LPS-stimulated hPTEC and hPods decreased pro-inflammatory gene expression including MCP-1, IL-6 and IL-8. CONCLUSIONS: Taken together, PBI-4050 improves systemic inflammation and indicators of glomerular and tubular injury in a model of LPS-induced AKI partly through GPR84, and may directly target specific renal cell types including PTEC’s and podocytes.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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) | 0.002 | 0.000 |
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".