Endocannabinoid System in Polycystic Kidney Disease

Abstract

Introduction: Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder characterized by renal cyst formation. A major pathological feature of ADPKD is the development of interstitial inflammation. The endocannabinoid (EC) system is present in the kidney and has recently emerged as an important player in inflammation and the pathogenesis of progressive kidney disease.

Methods: Data on ECs were collected using a validated mass spectrometry assay from a well-characterized cohort of 102 ADPKD patients (at baseline and after 2- and 4 years on standard vs. rigorous blood-pressure control) and compared to 100 healthy subjects.

Results: Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl-glycerol (2-AG), and their congeners in ADPKD patients. Baseline AEA concentration negatively associated with the progression of ADPKD as expressed by the yearly percent change in height-corrected total kidney volume and positively with the yearly change in renal function (measured as estimated glomerular filtration rate, ΔeGFR). AEA analog palmitoylethanolamide (PEA) is also associated positively with the yearly change in eGFR.

Discussion and conclusion: The results of the present study suggest that ADPKD patients present with lower levels of ECs and that reestablishing the normality of the renal EC system via augmentation of AEA, PEA, and 2-AG levels, either through the increase of their synthesis or through a reduction of their degradation, could be beneficial and may present a promising therapeutic target in said patients.

Keywords: 2-Arachidonoylglycerol; Anandamide; Autosomal dominant polycystic kidney disease; Endocannabinoids.

Figure 1:. Endocannabinoids and their main receptors.

The main endocannabinoids arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their congeners are part of larger families of lipids, the N-acylethanolamides (NAEs) and the 2-acylglycerols (2-AcGs), respectively. EC congeners are EC-like substances that do not elicit CB receptor activation [59], but rather permissively enhance AEA/2-AG effects, termed the “entourage effect” [60]. Numerous other members of these families signal through other G protein-coupled receptors (GPRs), ion channels and nuclear receptors, as shown. In addition, long-chain primary fatty acid amides, lipoamino acids and acyl neurotransmitters signal through some of the receptors used by NAEs and 2-AcGs. AEA congeners are AEA-like substances that do not elicit CB receptor activation [59], but rather permissively enhance AEA effects, which was termed the “entourage effect” [60]. Abbreviations: 2-AGE: 2-AG ether, Cav3: T-type Ca²⁺ channel, CB: cannabinoid receptor, DH-g-LEA: dihomo-γ-linolenoylethanolamide, LEA: linoleoylethanolamide, ODA: oleoyldopamine, OLA, oleamide, OEA: oleoylethanolamide, PEA: palmitoylethanolamide, PPAR: peroxisome proliferator-activated receptor, SEA: stearoylethanolamide, TRPV1: transient receptor potential cation channel subfamily V member 1.

Figure 2:

A) Changes in anandamide (log-transformed) over time (from baseline to 48 months) in individual patients stratified to either standard blood-pressure (BP) (120/70 to 130/80mm Hg, group 1, red) or rigorous BP control (95/60 to 110/75 mm Hg, group 2, green). B) Mean changes in anandamide levels (at baseline to 48 months) in patients stratified to either standard BP (treatment 1) or rigorous BP control (treatment 2). Data are presented as means ± standard error of the mean. Two-way repeated measures ANOVA revealed significant interaction treatment*time (p<0.05 adjusted for multiple testing). Abbreviations: AEA: anandamide.