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

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.

Diagnostic significance of hsa_circ_0000146 and hsa_circ_0000072 biomarkers for Diabetic Kidney Disease in patients with type 2 diabetes mellitus

“…CNR1 blockers were reported to normalize kidney functions and tubular injury in mice by reducing lipocalin 2, clusterin, cystatin C, and TNF expression [16] . Two neutral CNR1 receptor antagonists, AM6545 and AM4113, were previously reported to have renoprotective properties and lower kidney TGF levels [17] . CRP, an acute phase inflammatory protein, is associated with an increase in microalbuminuria and renal impairment in diabetic patients, suggesting a connection between CRP and DKD progression [5] [18] .…”

A Cross Talk between the Endocannabinoid System and Different Systems Involved in the Pathogenesis of Hypertensive Retinopathy

“…Keeping in view the significance of the ECS agonists, attempts were made to synthesize exogenous cannabinoids to mimic the effects of endocannabinoids either by facilitating biosynthesis of the EC agonists or avoiding their degradation by inhibiting hydrolyzing enzymes as shown in Figure 1 . Recent research has focused on blocking the receptors of the ECS such as Rimonabant (SR141716) [ 36 ], AM6545 and AM4113 [ 37 ], and antagonists for CB1 and the SR144528 antagonist for CB2 [ 38 ], while AM1241 has been employed as an agonist for CB2 receptors to obtain therapeutic responses. Other than synthesized agonists and antagonists for CB1 and CB2 receptors, researchers also focused on the inhibition of endocannabinoids degrading enzymes such as FAAH [ 39 , 40 , 41 ] and MAGL [ 42 , 43 ].…”

Endocannabinoid system: An untold story in hypertensive nephropathy

“…Keeping in view the significance of ECS agonists, attempts were made to synthesize exogenous cannabinoids to mimic the effects of endocannabinoids either by facilitating biosynthesis of EC agonists or avoiding their degradation by inhibiting hydrolyzing enzymes as shown in Figure 1. latest research focused on blocking the receptors of ECS like rimonabant (SR141716) [44], AM6545 and AM4113 [45] antagonists for CB1 and SR144528 antagonist for CB2 [46] while AM1241 have been employed as agonists for CB2 receptors to get therapeutic responses. Other than synthesized agonists and antagonists for CB1 and CB2 receptors, researchers also focused the inhibition of endocannabinoids degrading enzymes like FAAH [47][48][49] and MAGL [50,51].…”