Dual acting inhibitor of soluble epoxide hydrolase and Cyclooxygenase-2, attenuates glomerular injury in renal hypoplasia mice
Bibliographic record
Abstract
Glomerular diseases like focal and segmental glomerulosclerosis (FSGS) are the leading cause of chronic and end-stage kidney diseases. Although FSGS is associated with high morbidity and mortality, available treatments are limited, which emphasizes the need for novel therapy. We developed a dual inhibitor, PTUPB, that concurrently acts as a soluble epoxide hydrolase (sEH) inhibitor and a cyclooxygenase-2 (COX-2) inhibitor. In the current study, we investigated renal actions of PTUPB in a genetic renal hypoplasia FSGS model, ROP Os/+ mice. ROP Os/+ mice developed albuminuria and glomerular injury between 16 and 20 weeks of age with an 8-fold higher albumin/Cr ratio than wild-type ROP +/+ mice. Three groups were assessed: 20-week-old ROP +/+ mice, ROP Os/+ mice treated with vehicle, and ROP Os/+ mice treated with PTUPB (10 mg/kg/d, i.p.). After 4 weeks, urine, blood, and kidney tissue were collected in the mice groups for biochemical, molecular, and histological analysis. ROP Os/+ mice had 10-fold higher albuminuria than ROP +/+ mice, and PTUPB treatment markedly attenuated albuminuria in ROP Os/+ mice by 69 %. ROP Os/+ mice developed a glomerular injury with a 3-fold higher glomerular injury score and 10-fold higher glomerular expression of sclerotic marker fibronectin than ROP +/+ mice, and PTUPB treatment attenuated these by 40-50 %. We further demonstrated that there was significantly lower renal mRNA expression of nephrin, podocin, podoplanin, synaptopodin, and glomerular WT1 immunopositive cells in ROP Os/+ mice which was improved by PTUPB treatment in these mice. Glomerular permeability studies in isolated glomeruli determined that COX-2 metabolites of 8,9-epoxyeicosatrienoic acid (EET) increased glomerular permeability. PTUPB, 8,9-EET, or 8,9-EET analogs prevented angiotensin II-induced glomerular permeability and mesangial cell proliferation. These findings demonstrate that COX-2 metabolites harm the glomerulus, whereas 8,9-EET improves glomerular function. Lastly, kidney fibrosis and inflammation were increased in ROP Os/+ mice compared to ROP +/+ mice. PTUPB treatment to ROP Os/+ mice decreased kidney fibrosis and inflammation. These findings demonstrate that the dual inhibitor PTUPB that concurrently inhibits sEH and COX-2 is a potential treatment for FSGS and related glomerular 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".