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.

Basma G Eid,Thikryat Neamatallah,Hibah M Aldawsari,Abeer Hanafy,Alexandros Makriyannis,Kiran Vemuri,Gamal Abd El-Aziz,Hany M El-Bassossy,Atif Hasan,Lenah Binmahfouz

doi:10.3390/molecules26040866

Abstract

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.

Highlights

Metabolic syndrome (MetS), is a combination of metabolic abnormalities that commonly manifests as insulin resistance (IR), abdominal obesity, dyslipidemia and high blood pressure [1]
We have recently demonstrated that eight weeks of high-fructose and high-salt loading in Wistar rats was sufficient to induce a state of metabolic syndrome (MetS) manifested by obesity, hyperinsulinemia, hyperuricemia and dyslipidemia [28]
We have demonstrated that pre-treatment of these animals with either AM6545 or AM4113 caused an alleviation of the developed metabolic syndrome

Summary

Introduction

Metabolic syndrome (MetS), is a combination of metabolic abnormalities that commonly manifests as insulin resistance (IR), abdominal obesity, dyslipidemia and high blood pressure [1]. Patients with MetS are at a high risk of developing diabetes, atherosclerotic cardiovascular disease (CVD) and renal impairment [2]. All of these diseases represent serious and often fatal health conditions that are prevalent in most countries. The prevalence of MetS is increasing globally with over a billion people affected [3]. This increase is associated with physical inactivity, high-calorie food consumption and drinks supplemented with sugars [4,5]. The relationship between MetS and chronic kidney disease (CKD) is controversial. The incidence of CKD in patients with MetS is 2.6-fold higher than individuals without any MetS components [11]

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