Supplementary Material for: Endocannabinoid System in Polycystic Kidney Disease

<b><i>Introduction:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> Compared to healthy individuals, we found higher interleukins-6 and -1b as well as reduced plasma levels of anandamide (AEA), 2-arachidonoyl­glycerol (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. <b><i>Discussion and Conclusion:</i></b> 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.

<b><i>引言：</i></b> 常染色体显性遗传性多囊肾病（Autosomal dominant polycystic kidney disease, ADPKD）是一种常见的遗传性肾脏疾病，以肾囊肿形成为核心特征。ADPKD的主要病理特征之一为肾间质炎症的发生发展。内源性大麻素（endocannabinoid, EC）系统广泛存在于肾脏中，近年来被证实是炎症反应及进展性肾病发病机制中的关键调控通路。<b><i>方法：</i></b> 本研究采用经过验证的质谱检测方法，对102名纳入特征明确队列的ADPKD患者（分别在基线时、接受标准血压控制与严格血压控制后2年及4年采集样本）的内源性大麻素相关数据进行采集，并与100名健康受试者的对应数据进行对比分析。<b><i>结果：</i></b> 与健康个体相比，ADPKD患者的血浆白细胞介素-6、白细胞介素-1β水平显著升高，而花生四烯酸乙醇胺（anandamide, AEA）、2-花生四烯酰甘油（2-arachidonoylglycerol, 2-AG）及其同类物的血浆水平显著降低。基线AEA浓度与ADPKD的疾病进展呈负相关（以身高校正后总肾容积的年度百分比变化作为评估指标），与肾功能的年度变化呈正相关（以估算肾小球滤过率（estimated glomerular filtration rate, eGFR）的年度变化值ΔeGFR作为衡量标准）。AEA的类似物棕榈酰乙醇酰胺（palmitoylethanolamide, PEA）同样与eGFR的年度变化呈正相关。<b><i>讨论与结论：</i></b> 本研究结果提示，ADPKD患者体内内源性大麻素系统相关物质的水平偏低。通过促进AEA、PEA及2-AG的合成或抑制其降解以上调其水平，进而恢复肾脏内源性大麻素系统的稳态，或可对ADPKD患者产生获益，该策略或可成为该类患者极具前景的治疗靶点。