The emerging role of the endocannabinoid system in the pathogenesis and treatment of kidney diseases

Abstract

Endocannabinoids (eCBs) are endogenous lipid ligands that bind to cannabinoid receptors that also mediate the effects of marijuana. The eCB system is comprised of eCBs, anandamide, and 2-arachidonoyl glycerol, their cannabinoid-1 and cannabinoid-2 receptors (CB 1 and CB 2 , respectively), and the enzymes involved in their biosynthesis and degradation. It is present in both the central nervous system and peripheral organs including the kidney. The current review focuses on the role of the eCB system in normal kidney function and various diseases, such as diabetes and obesity, that directly contributes to the development of renal pathologies. Normally, activation of the CB 1 receptor regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments. In various mouse and rat models of obesity and type 1 and 2 diabetes mellitus, eCBs generated in various renal cells activate CB 1 receptors and contribute to the development of oxidative stress, inflammation, and renal fibrosis. These effects can be chronically ameliorated by CB 1 receptor blockers. In contrast, activation of the renal CB 2 receptors reduces the deleterious effects of these chronic diseases. Because the therapeutic potential of globally acting CB 1 receptor antagonists in these conditions is limited due to their neuropsychiatric adverse effects, the recent development of peripherally restricted CB 1 receptor antagonists may represent a novel pharmacological approach in treating renal diseases.Keywords: CB 1 receptor; CB 2 receptor; diabetic nephropathy; endocannabinoids; obesity; renal function. The endocannabinoid systemThe recreational, psychoactive, and medicinal effects of marijuana, many of which have important therapeutic potentials, have been recognized for thousands of years [1]. Yet, it is only in the last several decades that our understanding of these effects had grown following some landmark discoveries in the field of cannabinoid research. To date, more than 60 plant-derived cannabinoid molecules have been identified in marijuana [2], among which only Δ 9 -tetrahydrocannabinol (THC) is responsible for its psychoactive properties [3]. This initial discovery has allowed the synthesis of structurally modified molecules that have been used to study structure-activity relationships and reveal tight structural and steric selectivity in the biological actions of cannabinoids. Indeed, it took more than two decades to identify the THC binding site in the brain [4], which was later cloned and named cannabinoid-1 (CB 1 ) receptor [5]. In addition to the brain-type CB 1 receptor, a second cannabinoid receptor was identified in lymphoid tissue and was named CB 2 [6]. Both CB 1 and CB 2 receptors, which share a low level (44%) of sequence homology [6], are G protein-coupled receptors that mainly signal via G i /G o proteins, even though they may also activate G s , G q/11 , and G protein-independent signaling pathways [7]. These receptors are expressed in the brain [8][9][10], liver [11,...

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…842). The healthy kidney contains high basal levels of endocannabinoids, but its expression of CB2 receptors, instead, is still controversial.…”

Focus on cannabinoids and synthetic cannabinoids

“…The endocannabinoid system is present in the kidney, where it is involved in various renal functions . Normally, CB1R activation regulates renal vascular hemodynamics and stimulates the transport of ions and proteins in different nephron compartments.…”

Cannabinoid‐1 receptor deletion in podocytes mitigates both glomerular and tubular dysfunction in a mouse model of diabetic nephropathy

“…The endocannabinoid system (ECS) is comprised mainly of 2 membrane receptors (CB 1 R and CB 2 R) and their 2 major endogenous ligands, N‐arachidonoyl‐ethanolamine (anandamide or AEA) and 2‐arachidonoyl‐glycerol (2‐AG). In addition to its well‐documented role in obesity and its metabolic complications, the ECS has been implicated in the pathogenesis of CKD, including DN . Both CB 1 R and CB 2 R are expressed in the human and rodent kidney, particularly in mesangial cells, podocytes and proximal tubular cells .…”

“…Both CB 1 R and CB 2 R are expressed in the human and rodent kidney, particularly in mesangial cells, podocytes and proximal tubular cells . Enzymes responsible for the biosynthesis and degradation of endocannabinoids are also expressed in the kidney . We have previously reported that CB 1 R activation in podocytes mediates podocyte injury caused by hyperglycaemia and increased RAAS activity in a rat model of T2D .…”