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

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 injectio...

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Autores principales: Jacquot, Laetitia, Pointeau, Océane, Roger-Villeboeuf, Célia, Passilly-Degrace, Patricia, Belkaid, Rim, Regazzoni, Isaline, Leemput, Julia, Buch, Chloé, Demizieux, Laurent, Vergès, Bruno, Degrace, Pascal, Crater, Glenn, Jourdan, Tony
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479578/
https://www.ncbi.nlm.nih.gov/pubmed/37675364
http://dx.doi.org/10.3389/fneph.2023.1138416
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author Jacquot, Laetitia
Pointeau, Océane
Roger-Villeboeuf, Célia
Passilly-Degrace, Patricia
Belkaid, Rim
Regazzoni, Isaline
Leemput, Julia
Buch, Chloé
Demizieux, Laurent
Vergès, Bruno
Degrace, Pascal
Crater, Glenn
Jourdan, Tony
author_facet Jacquot, Laetitia
Pointeau, Océane
Roger-Villeboeuf, Célia
Passilly-Degrace, Patricia
Belkaid, Rim
Regazzoni, Isaline
Leemput, Julia
Buch, Chloé
Demizieux, Laurent
Vergès, Bruno
Degrace, Pascal
Crater, Glenn
Jourdan, Tony
author_sort Jacquot, Laetitia
collection PubMed
description 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.
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spelling pubmed-104795782023-09-06 Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy Jacquot, Laetitia Pointeau, Océane Roger-Villeboeuf, Célia Passilly-Degrace, Patricia Belkaid, Rim Regazzoni, Isaline Leemput, Julia Buch, Chloé Demizieux, Laurent Vergès, Bruno Degrace, Pascal Crater, Glenn Jourdan, Tony Front Nephrol Nephrology 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. Frontiers Media S.A. 2023-03-28 /pmc/articles/PMC10479578/ /pubmed/37675364 http://dx.doi.org/10.3389/fneph.2023.1138416 Text en Copyright © 2023 Jacquot, Pointeau, Roger-Villeboeuf, Passilly-Degrace, Belkaid, Regazzoni, Leemput, Buch, Demizieux, Vergès, Degrace, Crater and Jourdan https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Nephrology
Jacquot, Laetitia
Pointeau, Océane
Roger-Villeboeuf, Célia
Passilly-Degrace, Patricia
Belkaid, Rim
Regazzoni, Isaline
Leemput, Julia
Buch, Chloé
Demizieux, Laurent
Vergès, Bruno
Degrace, Pascal
Crater, Glenn
Jourdan, Tony
Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
title Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
title_full Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
title_fullStr Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
title_full_unstemmed Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
title_short Therapeutic potential of a novel peripherally restricted CB1R inverse agonist on the progression of diabetic nephropathy
title_sort therapeutic potential of a novel peripherally restricted cb1r inverse agonist on the progression of diabetic nephropathy
topic Nephrology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479578/
https://www.ncbi.nlm.nih.gov/pubmed/37675364
http://dx.doi.org/10.3389/fneph.2023.1138416
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