Cyclooxygenase (COX) Derived Oxylipins are Elevated in Models of Polycystic Kidney Disease, Indicating Potential for COX Inhibition to Treat Disease
Notice bibliographique
Résumé
Background Oxylipins (e.g. prostaglandins, leukotrienes) are bioactive lipids formed via oxidative metabolism of polyunsaturated fatty acids. The oxylipin profile is altered in the Han:SPRD‐ Cy rat and the pcy mouse, both models of nephronophthisis, a rare type of renal cyst disease. In these models, oxylipins formed via the cyclooxygenase (COX) pathway are elevated, while those produced via the lipoxygenase (LOX) and cytochrome P450 (CYP) pathways are reduced. Further, inhibition of COX oxylipin formation reduces disease progression in Han:SPRD‐ Cy rat, suggesting its potential for the treatment of these rare disorders. Polycystic kidney diseases (PKD) are more common forms of renal cyst diseases: autosomal dominant PKD (ADPKD) affects 1:400 to 1:1000 individuals and autosomal recessive PKD (ARPKD) affects 1:20,000 individuals. Since the oxylipin profile in PKD is not known, and since there are sex‐specific effects in PKD, the current studies were performed in orthologous models of PKD to determine whether oxylipins are altered in these more common disorders. Methods Mx1Cre + Pkd1 flox/flox (Pkd1) mice and Pkd2 WS25/− (Pkd2) mice are models of ADPKD, and PCK rats are a model of ARPKD. Four independent studies were performed. Male and female Pkd1 mice were injected with saline or polyinosinic polycytidylic acid (pI:pC) at 5 weeks (study#1) or 1 week (study#2) of age to induce disease, and kidneys obtained at 23 and 10 weeks of age, respectively. Kidneys from male and female Pkd2 mice (study#3) and male PCK rats (study#4) were obtained at 16 weeks of age. Over 100 oxylipins were analyzed by HPLC‐MS/MS and quantified using the stable isotope dilution technique. Results In Pkd1 mice induced at 5 weeks, renal levels of the COX metabolite prostaglandin (PG)E 2 was 27% higher in diseased compared to normal kidneys, and in Pkd1 mice induced at 1 week, PGD 2 , PGE 2 and 15k‐PGF 2α were 24, 25 and 65% higher in diseased kidneys, respectively. In Pkd2 mice, PGD 2 and PGF 2α were elevated in diseased kidneys by 98 and 33%, respectively, and in the PCK rat, PGE 2 and 6‐keto‐PGF 1α (PGI 2 metabolite) were elevated by 38 and 53%, respectively. COX oxylipins were higher in kidneys from females compared to males, but there were no sex differences in the disease effects on these oxylipins. In comparison to these consistently higher levels of COX derived oxylipins in diseased kidneys, the LOX and CYP derived oxylipin differences were fewer and less consistent. Conclusions COX oxylipins are elevated in all models of PKD examined, consistent with the findings in the Han:SPRD‐ Cy rat and pcy mouse models of nephronophthisis. As COX inhibition slows disease progression in those rare renal cyst disorders, the current results in PKD models suggest that COX inhibition also may be effective in the more common PKD disorders, for which no effective therapies currently exist. Support or Funding Information Canadian Institutes of Health Research (CIHR)
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».