矢志方调节NLRP3炎性体减轻尿酸性肾病肾小管损伤的炎症机制研究

It is reported that NLRP3 inflammasome is one of the cores in inflammation at present studies. Uric acid as a NLRP3 inflammasome agonist, activates NLRP3-ASC-caspase-1 axis and causes a cascade inflammation triggered by the release of reactive oxygen species from damaged mitochondria and cathepsins from phagosome.This is a new insight to uric acid nephropathy for Traditional Chinese Medicine(TCM).The basic pathology of TCM in uric acid nephropathy,is a syndrome of intermingled deficiency and excess,the syndrome of "phlegm，dampness and static blood binding together" plays a important role in the progression of disease.We confirmed that the TCM compound "Shizhi formula" could improve hyperuriacemia,renal tubular injury and inflammation,and reduce the mitochondrial damage of renal tubular epithelial cell,so we put forward to the hypothesis that the mechanism of ShiZhi formula alleviating renal tubular injury may be related to regulating the NLRP3 inflammasome as the core of the activation pathways. According to the well recognized method, the SD male rats are to be fed the diet contains 2% oxonic acid for 11 weeks to induce the model with chronic uric acid nephropathy,allopurinol as the control group,we test the effects of Shizhi formula on oxidative stress productions,NLRP3-ASC-caspase-1 axis,downstream inflammation factors IL-1β,IL-18 and renal tubular injury at different time point (3week,5week,7week,11week).The research will provide the important basis for applying "HuaTanQuShi,removing blood stasis" to treat and prevent renal tubular injury in uric acid nephropathy.

目前发现NLRP3炎性体是炎症反应的核心之一。尿酸作为NLRP3炎性体激动剂通过线粒体损伤释放的活性氧和组织蛋白酶途径激活NLRP3-ASC-caspase-1轴引起级联炎症反应。这一机制为防治尿酸性肾病肾小管损伤的研究提供了全新的视野。尿酸性肾病的基本病机为本虚标实，其中"痰湿瘀血互结"在病情发展中起着重要作用。在证实矢志方改善高尿酸血症、减轻大鼠肾小管损伤和炎症浸润及上皮细胞线粒体损伤的基础上，我们提出矢志方减轻尿酸性肾病大鼠肾小管损伤的炎症机制可能与调节NLRP3炎性体为核心的活化通路有关的假说。以含2%氧嗪酸的饲料诱导SD雄性大鼠尿酸性肾病模型为对象，设别嘌呤醇为对照，从不同时间节点研究矢志方调节氧化应激产物、NLRP3-ASC-caspase-1轴及下游炎症因子IL-1β和IL-18减轻肾小管损伤的机制。本课题将为矢志方"化痰祛湿、活血化瘀"防治尿酸性肾病肾小管损伤提供科学依据。

背景：随着高尿酸血症的发病率逐渐上升，尿酸及其诱导的肾脏炎症已成为慢性肾脏病进展为终末期肾病的重要因素。研究表明，尿酸能够通过激活NLRP3炎性体引起组织炎症。矢志方是治疗高尿酸血症的有效中药复方，研究其对高尿酸血症大鼠肾小管炎症损伤的保护作用机制十分必要。.主要研究内容：氧嗪酸钾制作高尿酸血症大鼠模型，以矢志方干预，以别嘌醇作为对照。实验第3，5，7，11周各组处死10只大鼠，研究矢志方对肾小管损伤、氧化应激和NLRP3-ASC-Caspase-1炎性轴的调节作用。.重要结果：矢志方可有效降低高尿酸血症大鼠血尿酸、保护肾小管损伤从而延缓肾小管间质纤维化，改善大鼠氧化应激，抑制NLRP30- ASC-Caspase-1炎性轴的活化及炎症因子的释放。.关键数据：矢志方可有效降低高尿酸血症大鼠血尿酸（p<0.05）、减少肾组织活性氧释放(p<0.05)，抑制NLRP30－ASC-Caspase-1炎性轴的蛋白表达(p<0.05)及炎症因子IL-1β和IL-18的释放（p<0.05）。.科学意义：为矢志方“化痰祛湿，活血化淤”防治高尿酸血症及尿酸性肾病肾小管损伤提供科学依据。