Abstract
Chronic kidney disease (CKD) concerns millions of individuals worldwide, with few therapeutic strategies available to date. Recent evidence suggests that the endocannabinoid system (ECS) could be a new therapeutic target to prevent CKD. ECS combines receptors, cannabinoid receptor type 1 (CB1R) and type 2 (CB2R), and ligands. The most prominent receptor within the kidney is CB1R, its endogenous local ligands being anandamide and 2-arachidonoylglycerol. Therefore, the present review focuses on the therapeutic potential of CB1R and not CB2R. In the normal kidney, CB1R is expressed in many cell types, especially in the vasculature where it contributes to the regulation of renal hemodynamics. CB1R could also participate to water and sodium balance and to blood pressure regulation but its precise role remains to decipher. CB1R promotes renal fibrosis in both metabolic and non-metabolic nephropathies. In metabolic syndrome, obesity and diabetes, CB1R inhibition not only improves metabolic parameters, but also exerts a direct role in preventing renal fibrosis. In non-metabolic nephropathies, its inhibition reduces the development of renal fibrosis. There is a growing interest of the industry to develop new CB1R antagonists without central nervous side-effects. Experimental data on renal fibrosis are encouraging and some molecules are currently under early-stage clinical phases (phases I and IIa studies). In the present review, we will first describe the role of the endocannabinoid receptors, especially CB1R, in renal physiology. We will next explore the role of endocannabinoid receptors in both metabolic and non-metabolic CKD and renal fibrosis. Finally, we will discuss the therapeutic potential of CB1R inhibition using the new pharmacological approaches. Overall, the new pharmacological blockers of CB1R could provide an additional therapeutic toolbox in the management of CKD and renal fibrosis from both metabolic and non-metabolic origin.
Highlights
Chronic kidney disease (CKD) is an important problem worldwide and remains a burden for public health [1]
New therapeutic classes have improved the management of diabetic nephropathy, which is the main cause of CKD and end-stage renal disease (ESRD) worldwide [3], sodium glucose co-transporter 2 (SGLT2) inhibitors [4,5,6,7,8] and glucagon-like peptide-1 receptor (GLP-1R) agonists [9, 10]
In the ureteral obstruction (UUO) model, we found that whereas CB1 expression was drastically increased in the tubules, interstitium and glomeruli, cannabinoid receptor type 1 (CB1R) blockade significantly reduced the increase of renal fibrosis through a direct paracrine/autocrine role of CB1R in myofibroblasts with no strong evidence for a direct role of CB1R expressed in tubules [12]
Summary
Chronic kidney disease (CKD) is an important problem worldwide and remains a burden for public health [1]. CB2R is Abbreviations: 2-AG, 2-arachidonoylglycerol; ACC, acetyl-CoA carboxylase; AEA, anandamide; AMPK, AMP-activated kinase; Ang II, angiotensin II; AT1, Ang II type 1 receptors; BBB, blood brain barrier; BP, blood pressure; CAD, chronic kidney allograft dysfunction; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 1; CCR2, CC chemokine receptor 2; CKD, chronic kidney disease; COX-2, cyclooxygenase type 2; DAGL, sn-1-specific diacylglycerol lipase; ECS, endocannabinoid system; ESRD, end-stage renal disease; FAAH, fatty acid amide hydrolase; GFR, glomerular filtration rate; GLUT2, glucose transporter 2; HK2, human proximal tubular cell line; HP, hemopressin; HTN, hypertension; IHC, immunohistochemical assay; LKB1, tumor suppressor liver kinase B1; MAGL, monoacylglycerol lipase; MCP-1, monocyte chemoattractant protein-1; NAPE, N-arachidonoyl phosphatidyl ethanolamine; NAPE-PLD, NAPE-specific phospholipase D; PIP2, 2-arachidonoyl-phosphatidylinositol 4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; RAS, renin angiotensin system; SGLT2, sodium glucose co-transporter 2; SHR, spontaneously hypertensive rat; RPTC, renal proximal tubular epithelial cells; RT-PCR, Reverse transcription and polymerase chain reaction; SR141716A, rimonabant; STZ, streptozotocin; TAL, thick ascending limb; THC, tetrahydrocannabinol; TGFb, transforming growth factor b; TRPV1, transient receptor potential vanilloid type I channels; UUO, unilateral ureteral obstruction; WB, western blot; WIN, WIN55,212-2; ZDF, Zucker diabetic fatty. We will discuss the therapeutic potential of CB1R inhibition using the newest pharmacological approaches
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