Susceptibility of both female and male mice to acute kidney injury (AKI): protective effect of P2Y14 receptor inhibition
Notice bibliographique
Résumé
While sex is increasingly considered as a critical variable in kidney health, female mice and patients remain underrepresented in preclinical and clinical studies. Ischemic-induced AKI is a frequent complication in hospitalized patients. Here, we assessed the severity of AKI in female and male C57BL/CBAF1mice subjected to bilateral ischemia-reperfusion injury (BIRI), with a clamping time of 35 min and reperfusion for 24 h (n ≥ 8 mice per group). SHAM surgeries were performed without clamping. Based on plasma creatinine (pCre), females showed an apparent AKI protection versus males (females: fold increase of pCre-BIRI/SHAM = 1.6, p=0.18, versus males: pCre-BIRI/SHAM = 7.8, p=0.005). BIRI induced a 2.8-fold increase in blood urea nitrogen (BUN) versus SHAM in females (p=0.04), and a 5.2-fold increase in males (p<0.001). A significant increase in the percentage of severely damaged proximal tubules (PTs), characterized by a complete loss of AQP1 polarity, was observed in both females (61% BIRI vs 0% SHAM, p = 0.03) and males (45% BIRI vs 0% SHAM, p = 0.001). WB showed an increase in the expression of acyl-CoA synthetase long-chain family member 4 (ASCL4), indicating induction of ferroptosis by BIRI, in females and males. We previously showed that the pro-inflammatory P2Y14 receptor is a key driver of AKI in male mice. Here, both females and males treated with the P2Y14 antagonist, PPTN, showed reduced severity of BIRI-induced AKI versus the non-treated group, as evidenced by: 1) reduced BUN elevation (BIRI-PPTN = 7.82 mmol/L versus BIRI-vehicle = 16.02 mmol/L, p=0.03 in females, and BIRI-PPTN = 18.22 mmol/L versus BIRI-vehicle = 33.62, p=0.05 in males); 2) reduction in the percentage of damaged PTs (BIRI-PPTN = 1.1%, p=0.002 versus BIRI-vehicle in females, and BIRI-PPTN= 16.4%, p=0.03 versus BIRI-vehicle in males); 3) expression of ASCL4 similar to that of SHAM levels in females and males. Interestingly, a lower dose of PPTN was required in females (5 mg/kg/day) versus males (10 mg/kg/day) to achieve maximal response. In addition, preliminary results showed a BIRI-induced increase in Ly6G positive neutrophils in kidney sections from males and females, and reduction of neutrophil numbers upon PPTN treatment. We are currently analyzing, by LC-MS/MS, the renal expression of lipids potentially involved in the inflammatory response (prostaglandins, leukotrienes, endocannabinoids and their congeners) after BIRI with and without PPTN treatment. Overall, our results show that both females and males can develop ischemic-AKI, and that pCre is a poor marker of AKI in females. Finally, this study shows that attenuation of renal inflammation via P2Y14 inhibition protects against ferroptosis and reduces the extent of kidney dysfunction and damage following ischemia-reperfusion injury in both female and male mice. CIHR PJT-183711-2022 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,001 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,002 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,010 | 0,002 |
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 ».