Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome
The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 wee...
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MDPI AG
2021-02-01
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| author | Basma G. Eid Thikryat Neamatallah Abeer Hanafy Hany M. El-Bassossy Lenah Binmahfouz Hibah M. Aldawsari Atif Hasan Gamal Abd El-Aziz Kiran Vemuri Alexandros Makriyannis |
| author_facet | Basma G. Eid Thikryat Neamatallah Abeer Hanafy Hany M. El-Bassossy Lenah Binmahfouz Hibah M. Aldawsari Atif Hasan Gamal Abd El-Aziz Kiran Vemuri Alexandros Makriyannis |
| author_sort | Basma G. Eid |
| collection | DOAJ |
| description | The role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action. |
| first_indexed | 2024-03-09T05:21:22Z |
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| id | doaj.art-92c098f9897b48249f94b5e62c63f2c0 |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T05:21:22Z |
| publishDate | 2021-02-01 |
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| series | Molecules |
| spelling | doaj.art-92c098f9897b48249f94b5e62c63f2c02023-12-03T12:40:31ZengMDPI AGMolecules1420-30492021-02-0126486610.3390/molecules26040866Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic SyndromeBasma G. Eid0Thikryat Neamatallah1Abeer Hanafy2Hany M. El-Bassossy3Lenah Binmahfouz4Hibah M. Aldawsari5Atif Hasan6Gamal Abd El-Aziz7Kiran Vemuri8Alexandros Makriyannis9Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, EgyptDepartment of Pharmacology and Toxicology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Pharmaceutics, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaDepartment of Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh 33516, EgyptDepartment of Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi ArabiaCenter for Drug Discovery, Northeastern University, Boston, MA 02115, USACenter for Drug Discovery, Northeastern University, Boston, MA 02115, USAThe role of cannabinoid receptors in nephropathy is gaining much attention. This study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with metabolic syndrome (MetS). MetS was induced in rats by high-fructose high-salt feeding for 12 weeks. AM6545, the peripheral silent antagonist and AM4113, the central neutral antagonist were administered in the last 4 weeks. At the end of study, blood and urine samples were collected for biochemical analyses while the kidneys were excised for histopathological investigation and transforming growth factor beta 1 (TGFβ1) measurement. MetS was associated with deteriorated kidney function as indicated by the elevated proteinuria and albumin excretion rate. Both compounds equally inhibited the elevated proteinuria and albumin excretion rate while having no effect on creatinine clearance and blood pressure. In addition, AM6545 and AM4113 alleviated the observed swelling and inflammatory cells infiltration in different kidney structures. Moreover, AM6545 and AM4113 alleviated the observed histopathological alterations in kidney structure of MetS rats. MetS was associated with a ten-fold increase in urine uric acid while both compounds blocked this increase. Furthermore, AM6545 and AM4113 completely prevented the collagen deposition and the elevated expression of the TGFβ1 seen in MetS animals. In conclusion, AM6545 and AM4113, possess reno-protective effects by interfering with TGFβ1-mediated renal inflammation and fibrosis, via peripheral action.https://www.mdpi.com/1420-3049/26/4/866metabolic syndromecannabinoidsAM6545AM4113kidneyrats |
| spellingShingle | Basma G. Eid Thikryat Neamatallah Abeer Hanafy Hany M. El-Bassossy Lenah Binmahfouz Hibah M. Aldawsari Atif Hasan Gamal Abd El-Aziz Kiran Vemuri Alexandros Makriyannis Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome Molecules metabolic syndrome cannabinoids AM6545 AM4113 kidney rats |
| title | Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome |
| title_full | Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome |
| title_fullStr | Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome |
| title_full_unstemmed | Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome |
| title_short | Interference with TGFβ1-Mediated Inflammation and Fibrosis Underlies Reno-Protective Effects of the CB1 Receptor Neutral Antagonists AM6545 and AM4113 in a Rat Model of Metabolic Syndrome |
| title_sort | interference with tgfβ1 mediated inflammation and fibrosis underlies reno protective effects of the cb1 receptor neutral antagonists am6545 and am4113 in a rat model of metabolic syndrome |
| topic | metabolic syndrome cannabinoids AM6545 AM4113 kidney rats |
| url | https://www.mdpi.com/1420-3049/26/4/866 |
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