دورية أكاديمية
أعرض في EDS

Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy.

التفاصيل البيبلوغرافية
العنوان: Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy.
المؤلفون: Jacquot L; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Pointeau O; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Roger-Villeboeuf C; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Passilly-Degrace P; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Belkaid R; ImaFlow core facility, UMR1231 INSERM, University of Burgundy, Dijon, France., Regazzoni I; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Leemput J; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Buch C; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Demizieux L; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Vergès B; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Degrace P; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France., Crater G; Inversago Pharma Inc, Montréal, Québec, Canada., Jourdan T; Pathophysiology of Dyslipidemia research group, National Institute of Health and Medical Research (INSERM) Unité Mixte de Recherche (UMR1231) Lipids, Nutrition, Cancer, Université de Bourgogne Franche-Comté, Dijon, France.
المصدر: Frontiers in nephrology [Front Nephrol] 2023 Mar 28; Vol. 3, pp. 1138416. Date of Electronic Publication: 2023 Mar 28 (Print Publication: 2023).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Frontiers Media S.A Country of Publication: Switzerland NLM ID: 9918469487906676 Publication Model: eCollection Cited Medium: Internet ISSN: 2813-0626 (Electronic) Linking ISSN: 28130626 NLM ISO Abbreviation: Front Nephrol Subsets: PubMed not MEDLINE
أسماء مطبوعة: Publication: Lausanne, Switzerland : Frontiers Media S.A., [2021]-
مستخلص: Objective: This study assessed the efficacy of INV-202, a novel peripherally restricted cannabinoid type-1 receptor (CB1R) inverse agonist, in a streptozotocin-induced type-1 diabetes nephropathy mouse model.
Methods: Diabetes was induced in 8-week-old C57BL6/J male mice via intraperitoneal injection of streptozotocin (45 mg/kg/day for 5 days); nondiabetic controls received citrate buffer. Diabetic mice were randomized to 3 groups based on blood glucose, polyuria, and albuminuria, and administered daily oral doses for 28-days of INV-202 at 0.3 or 3 mg/kg or vehicle.
Results: INV-202 did not affect body weight but decreased kidney weight compared with the vehicle group. While polyuria was unaffected by INV-202 treatment, urinary urea (control 30.77 ± 14.93; vehicle 189.81 ± 31.49; INV-202 (0.3 mg/kg) 127.76 ± 20; INV-202 (3 mg/kg) 93.70 ± 24.97 mg/24h) and albumin (control 3.06 ± 0.38; vehicle 850.08 ± 170.50; INV-202 (0.3 mg/kg) 290.65 ± 88.70; INV-202 (3 mg/kg) 111.29 ± 33.47 µg/24h) excretion both decreased compared with vehicle-treated diabetic mice. Compared with the vehicle group, there was a significant improvement in the urinary albumin to creatinine ratio across INV-202 groups. Regardless of the dose, INV-202 significantly reduced angiotensin II excretion in diabetic mice. The treatment also decreased Agtr1a renal expression in a dose-dependent manner. Compared with nondiabetic controls, the glomerular filtration rate was increased in the vehicle group and significantly decreased by INV-202 at 3 mg/kg. While the vehicle group showed a significant loss in the mean number of podocytes per glomerulus, INV-202 treatment limited podocyte loss in a dose-dependent manner. Moreover, in both INV-202 groups, expression of genes coding for podocyte structural proteins nephrin ( Nphs1 ), podocin ( Nphs2 ), and podocalyxin ( Pdxl ) were restored to levels similar to nondiabetic controls. INV-202 partially limited the proximal tubular epithelial cell (PTEC) hyperplasia and normalized genetic markers for PTEC lesions. INV-202 also reduced expression of genes contributing to oxidative stress ( Nox2 , Nox4 , and P47phox ) and inflammation ( Tnf ). In addition, diabetes-induced renal fibrosis was significantly reduced by INV-202.
Conclusions: INV-202 reduced glomerular injury, preserved podocyte structure and function, reduced injury to PTECs, and ultimately reduced renal fibrosis in a streptozotocin-induced diabetic nephropathy mouse model. These results suggest that INV-202 may represent a new therapeutic option in the treatment of diabetic kidney disease.
Competing Interests: Author GC is the Chief Medical Officer at Inversago Pharma, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Inversago Pharma, Inc. The funder had the following involvement with the study: study design.
(Copyright © 2023 Jacquot, Pointeau, Roger-Villeboeuf, Passilly-Degrace, Belkaid, Regazzoni, Leemput, Buch, Demizieux, Vergès, Degrace, Crater and Jourdan.)
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فهرسة مساهمة: Keywords: CB1 receptors; diabetes; fibrosis; inverse agonism; nephropathy; peripherally-restricted
تواريخ الأحداث: Date Created: 20230907 Latest Revision: 20230908
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC10479578
DOI: 10.3389/fneph.2023.1138416
PMID: 37675364
قاعدة البيانات: MEDLINE
الوصف
تدمد:2813-0626
DOI:10.3389/fneph.2023.1138416