Inhibition of the inflammasome ameliorates orthologous polycystic kidney disease

ADPKD is the most common genetic renal disease, leading to renal failure in the vast majority of affected individuals. Standard therapy consists of blood pressure control and salt restriction. Tolvaptan further delays renal failure but side effects prevent its widespread use. Novel therapeutic approaches are needed. Recent evidence has identified inflammation as an important driver of ADPKD. Here we show a strong inflammatory signature in transcriptomes of early ADPKD in the mouse. IL1ß and IL18, effectors of inflammasome activation, are among the top upregulated transcripts. Inflammasomes act as part of the innate immune response to danger signals, including crystals. Induction of calcium oxalate crystals through dietary intervention in Pkd1 mutant mice aggravated the cystic phenotype. Treatment of Pkd1 mutant mice with the inflammasome inhibitor MCC950 significantly ameliorated the ADPKD phenotype. Analogous results were obtained through genetic silencing of the essential inflammasome component Asc in ADPKD mice. Interference with inflammasome activation in the ADPKD animals resulted in better renal function and decreased IL18 excretion in the urine. These findings identify inflammasome inhibition as a promising concept for the treatment of ADPKD. Overall design: We performed a transcriptional screen in mice with a time dependent targeted deletion of Pkd1. Pkd1flox/flox.Pax8rtTA.Tet-O-Cre mice underwent tetracycline induced tubular deletion of Pkd1 during postnatal week 5 and 6. At 10 weeks, the kidneys were analyzed by RNAseq and the transcripts compared to kidneys from non-cystic Pkd1flox/flox.Tet-O-Cre control animals lacking Pax8rtTA.

常染色体显性遗传性多囊肾病（ADPKD）是最常见的遗传性肾脏疾病，可导致绝大多数患者进展为肾衰竭。临床标准治疗方案包括血压管控与食盐限制。托伐普坦（Tolvaptan）可进一步延缓肾衰竭进程，但因其不良反应限制了临床广泛应用，故亟需开发新型治疗策略。

近期研究证实炎症是ADPKD的重要致病驱动因素。本研究在小鼠早期ADPKD模型的转录组（transcriptome）中检测到显著的炎症特征谱。炎症小体（inflammasome）激活的效应因子IL-1β与IL-18，位列上调幅度最显著的转录本之列。炎症小体作为固有免疫应答的核心组分，可识别包括晶体在内的各类危险信号。通过饮食干预在Pkd1突变小鼠体内诱导草酸钙晶体形成，可加重其囊性表型。采用炎症小体抑制剂MCC950处理Pkd1突变小鼠，可显著改善ADPKD表型；通过基因沉默ADPKD模型小鼠体内炎症小体必需组分Asc的表达，也得到了一致的实验结果。抑制ADPKD模型小鼠的炎症小体激活，可改善其肾功能，并降低尿液中IL-18的排泄水平。上述研究结果证实，靶向抑制炎症小体是极具潜力的ADPKD治疗策略。

实验整体设计：本研究对携带时间依赖性Pkd1靶向敲除的小鼠开展转录组筛选。Pkd1flox/flox.Pax8rtTA.Tet-O-Cre小鼠在出生后第5、6周经四环素诱导，实现肾小管上皮细胞的Pkd1基因敲除。待小鼠生长至10周龄时，提取肾脏组织进行RNA测序（RNA-seq），并将其转录组数据与不携带Pax8rtTA的非囊性Pkd1flox/flox.Tet-O-Cre对照小鼠的肾脏组织转录组进行对比分析。