MO608: INV-202, A CB1 Receptor Blocker, Reduces Renal Injury in A Murine Model of Streptozotocin (STZ)-Induced Type-1 Diabetes
Notice bibliographique
Résumé
Abstract BACKGROUND AND AIMS Renal diseases remain a burden for Public Health and chronic kidney disease (CKD) affects several millions of individuals worldwide. Diabetic Nephropathy (DN) is the most frequent consequence of diabetes and is characterized by an increase in urinary albumin excretion and progressive loss of renal function associated with glomerular basement membrane thickening, mesangial expansion, nodular glomerular sclerosis and tubulointerstitial fibrosis. To date, there are few treatments that can prevent its progression. Indeed, current therapeutic approaches including RAAS blockers, SGLT2 inhibitors or both approaches combined do not fully abrogate DN progression. A growing body of experimental evidence suggests that modulation of the endocannabinoid system, and in particular its type 1 receptor (CB1R), may be a therapeutic tool in the management of CKD and more particularly DN. CB1R blockade represents a potential therapeutic modality in the fight against obesity, diabetes and their metabolic sequelae. In kidney, CB1R inhibition promotes a reduction in albuminuria, renal fibrosis and preserves renal function in both obesity-induced and diabetic nephropathy in mice mainly through a direct action of CB1R in podocytes and/or proximal tubules. INV-202 is a peripherally acting Cannabinoid receptor-1 (CB1r) inverse agonist that is under clinical development for the treatment of diseases associated with diabetes and metabolic syndrome. Here we report the effects of INV-202 on renal function and associated parameters in a preclinical model of diabetic nephropathy. METHOD Twelve weeks after the initiation of diabetes using streptozotocin, C57BL6/J mice (8 per treatment group) were randomized to receive a daily oral dose of INV-202, 0.3 mg/kg and 3 mg/kg or vehicle for 4 weeks. Five mice not treated with STZ were used as a nondiabetic control. At the end of treatment, animals were sacrificed. Urinary albumin-to-creatinine ratio (ACR), renal matrix remodelling, glomerular filtration and interstitial fibrosis were assessed in addition to glucose levels, body weight and organ weights. RESULTS After 28 days of treatment, there was no significant effect on hyperglycemia or body weight with either dose of INV-202. Renal and hepatic weights were reduced while heart weight was unaffected. This remained true when normalizing for tibial length. Compared with vehicle-treated diabetic mice, INV-202-challenged mice displayed a marked decrease in many clinical features of DN such as albuminuria, albumin-to-creatinine ratio, urinary urea, loss of glomerular filtration rate and renal hypertrophy. Interestingly, we also found an improvement in both podocyte and proximal tubular cells morphology and health markers that were likely responsible for the improvement previously mentioned. In addition, INV-202 led to a downregulation of the angiotensin II receptor expression as well as a reduced urinary excretion, suggesting an inhibitory effect of this compound on the angiotensin II-mediated renal dysfunction in the context of DN. Furthermore, INV-202 also led to a drastic reduction in renal inflammation and oxidative stress markers that are known to be highly involved in the pathogenesis of DN. Finally, despite the limitation of our model in regard to interstitial fibrosis development, we could observe a marked anti-fibrotic effect of INV-202. CONCLUSION Treatment with INV-202 reduced the progression of nephropathy in STZ-induced diabetic mice. Improvements in kidney size, function and histology, with corresponding gene expression, were noted with both doses of INV-202. Further work to explore the effect of INV-202 in humans is warranted.
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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) | 0,001 | 0,001 |
| 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 | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 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 ».