Decreasing the viability of cyst-lining cells via inhibition of Ire1α as a novel strategy to treat autosomal-dominant polycystic kidney disease (ADPKD)

常染色体显性遗传性多囊肾病(ADPKD)是最常见的遗传性肾病，发病个体比例为1：400~1：1,000。它占所有遗传性肾囊性疾病的90%以上，以双侧肾囊肿为特征。这些囊肿通常在几十年内缓慢生长和扩大，导致肾脏总体积显著增加，进行性肾脏损伤，并最终在生命的第六个十年左右发生终末期肾脏疾病(ESRD)。ADPKD最常见的肾外表现是多囊肝病，它也可以作为一个独立的遗传实体发生，常染色体显性遗传性多囊肝病(ADPLD)。以往的研究表明，尽管ADPLD和ADPKD的肾脏表现不同，但它们具有以多囊蛋白-1(PC1)活性为中心的共同的潜在分子遗传学机制。PC1是与ADPKD相关的主要基因PKD1的蛋白质产物。ADPKD在细胞水平上表现为隐性。因此，含有胚系突变的细胞的正常PC1等位基因的体细胞二次撞击启动或加速了包囊的形成。研究表明，IRE1α-XBP1通路是内质网未折叠蛋白应答中最保守的分支，它在导致ADPLD的基因Sec63缺乏诱导的包囊形成中起到保护作用。这是通过上调依赖于XBP1的伴侣蛋白来优化错误折叠的PC1的ER折叠环境来实现的。我们最近未发表的数据显示，XBP1是PKD1的直接遗传相互作用因子，可能通过使PC1失活来意外地促进ADPKD的进展。我们假设XBP1的上调保护了PKD1缺陷的囊泡细胞免于凋亡，这反过来又促进了囊泡的生长。因此，PKD1/XBP1的双重失活导致了囊壁上皮细胞的特异性凋亡，而不影响细胞的增殖。初步数据有力地表明，体内调节稳态IRE1XBP1信号的途径可能具有治疗潜力。这种保护作用是通过选择性地促进细胞凋亡来实现的，这些细胞在PKD1中获得了二次打击，这些细胞负责囊性病变的发展，最终导致多囊肾和肝病。在这些研究的基础上，本研究的目的是探讨IRE1PK1-XBP1-双基因敲除依赖的囊性衬里细胞凋亡的潜在机制以及化学调控IRE1PK1-XBP1通路对囊变的影响，以及α失活对由α或Pkhd1缺失引起的多囊肝病进展的影响。我们假设抑制IRE1α-XBP1的途径具有治疗ADPKD的新方法的潜力。

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1:400 to 1:1,000 individuals. It accounts for over 90% of all hereditary renal cystic diseases and is characterized by the presence of bilateral renal cysts. These cysts typically grow and expand slowly over decades, resulting in significantly increased total kidney volume, progressive renal injury and ultimately end stage renal disease (ESRD) around the sixth decade of life. The most common extrarenal manifestation of ADPKD is polycystic liver disease, which can also occur as an independent genetic entity, autosomal-dominant polycystic liver disease (ADPLD). Previously, it has been demonstrated that ADPLD and ADPKD share a common underlying molecular genetic mechanism centered on the activity of polycystin-1 (PC1) despite differential degree of kidney manifestations. PC1 is the protein product of the primary gene linked to ADPKD, Pkd1. ADPKD appears to be recessive at the cellular level. Therefore, somatic second hits in the normal PC1-allele of cells containing the germline mutation initiate or accelerate the formation of cysts. It became evident that the Ire1α-XBP1 pathway, the most conserved branch of the endoplasmic reticulum (ER) unfolded protein response (UPR), plays a protective role in cyst formation induced by Sec63 deficiency, one of the genes causing ADPLD. This is accomplished by an optimization of the ER-folding environment of misfolded PC1 via upregulation of chaperone proteins dependent on XBP1. Our recent unpublished data has revealed that XBP1 is a direct genetic interactor of Pkd1 and may surprisingly promote the progression of ADPKD via inactivation of PC1. We hypothesize that upregulation of XBP1 protects Pkd1-deficient cyst cells from apoptosis, which in turn promotes cyst growth. Consequently, double inactivation of Pkd1/XBP1 leads to specific apoptosis of cyst lining epithelia without any impact on proliferation. Preliminary data strongly suggests that avenues modulating homeostatic Ire1α-XBP1 signaling in vivo may hold therapeutic potential. This protective effect is accomplished by selectively promoting the apoptosis of cells that have acquired second hits in Pkd1, and which are responsible for the development of cystic lesions that eventually lead to polycystic kidney and liver disease. Based on these studies the aim of this project is to investigate: a) the underlying mechanism of Ire1α-XBP1-double knockout dependent cyst-lining cell apoptosis and the impact of chemical modulation of the Ire1α-XBP1 pathway on cyst progression and b) the effect of XBP1 inactivation on the progression of polycystic liver disease due to Pkd1 or Pkhd1 deletion. We hypothesize that avenues that inhibit Ire1α-XBP1 hold therapeutic potential for a novel treatment of ADPKD.