Beclin-1介导的自噬通路在常染色体显性多囊肾病进展中的机制研究

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic disease in humans and the fourth leading cause of end-stage renal disease in adults. The increased survival ability and continuing abnormal proliferation of epithelial cells in ADPKD are crucial for the disease progression. Our preliminary work found ①the increased amount of autophagosomes and ② up-regulation of Beclin-1 and LC3-II levels in ADPKD mice model, as well as ③significantly reduction of the amount of cyst epithelial cells under hypoxia culture with specific autophagy inhibitor. Considering the fact that autophagy is one of the important mechanisms of cell survival, we hypothesized that Beclin-1 pathway induces the enhanced survival ability resistant to the unhealthy micro-environment via autophagy process, which promotes the disease progression of ADPKD. To test this hypothesis, we firstly confirm autophagy and the expression of Beclin-1/Vps34/LC3-II pathway and its relative regulatory genes. In the next step, the expression of Beclin-1 will artificially be up- and down-regulated to test the impact of Beclin-1 pathway induced autophagy on the ADPKD progression. This study aims to broaden our horizons of the mechanism concerning ADPKD progression, and to provide the basis for the new ADPKD treatment regimen by targeting Beclin-1 pathway.

常染色体显性多囊肾病（ADPKD）是最常见的遗传性肾病，囊肿上皮细胞存活能力增强且持续增殖是多囊肾病情进展的重要原因。前期工作发现①ADPKD小鼠肾脏囊肿上皮细胞出现大量自噬体；②且小鼠肾脏Beclin-1及LC3-II蛋白表达明显上调；③自噬通路抑制剂可明显减少低氧培养下的囊肿上皮细胞数目。而自噬是公认的细胞存活的重要机制之一，因此我们推测Beclin-1通路可通过促进自噬保护提高囊肿上皮细胞对不良微环境的耐受力，进而促进ADPKD的病情进展。为验证该推断，拟在多囊肾小鼠模型及低氧培养的囊肿上皮细胞中观察自噬现象和Beclin-1/Vps34/LC3-II通路的表达；通过上调及下调Beclin-1，观察Beclin-1通路介导的自噬保护对ADPKD病情进展的影响。本研究不仅深化了对ADPKD病情进展机制的认识，还为研究以Beclin-1通路为干预靶点的ADPKD治疗新方案提供依据。

常染色体显性多囊肾病（ADPKD）是最常见的遗传性肾病，囊肿上皮细胞存活能力增强且持续增殖是多囊肾病情进展的重要原因。前期工作发现ADPKD小鼠肾脏囊肿上皮细胞出现大量自噬体，小鼠肾脏Beclin-1及LC3-II蛋白表达明显上调，自噬通路抑制剂可明显减少低氧培养下的囊肿上皮细胞数目。推测Beclin-1介导相关自噬通路参与促进ADPKD的病情进展。本研究在多囊肾小鼠模型及囊肿上皮细胞中观察雷公藤内酯醇（TP）可有效抑制囊肿发展，与TP干预后Beclin-1介导的自噬通路改变相关；进一步发现，Beclin-1通路的上游mTOR通路在TP干预后磷酸化mTOR和S6核糖体异常增高，可能是ADPKD自噬异常及囊肿细胞增殖的潜在机制。SENP1蛋白可减少凋亡，对DDP模拟的肾脏损伤具有一定保护作用，推测SENP1或参与了ADPKD缺血或药物等压力下肾脏细胞的生存。最后通过临床治疗研究，验证了将Beclin-1介导的自噬通路作为靶点的TP作为干预药物，具有保护ADPKD患者肾脏功能、延缓ADPKD病情进展的作用。本研究不仅深化了对ADPKD病情进展机制的认识，还为以自噬相关通路为ADPKD干预靶点的治疗新方案提供依据。