PDF(Pubmed)
Abstract：
Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multiprotein complexes. Deletion of several IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult autosomal dominant polycystic kidney disease (ADPKD) mouse models. However, deletion of an IFT-A adaptor, Tulp3, attenuates PKD severity in adult mice only. These studies indicate that dysfunction of specific cilia components has potential therapeutic value. To broaden our understanding of cilia dysfunction and its therapeutic potential, we investigate the role of global deletion of an IFT-A gene, Ttc21b, in juvenile and adult mouse models of ADPKD. Both juvenile (postnatal day 21) and adult (six months of age) ADPKD mice exhibited kidney cysts, increased kidney weight/body weight ratios, lengthened kidney cilia, inflammation, and increased levels of the nutrient sensor, O-linked β-N-acetylglucosamine (O-GlcNAc). Deletion of Ttc21b in juvenile ADPKD mice reduced cortical collecting duct cystogenesis and kidney weight/body weight ratios, increased proximal tubular and glomerular dilations, but did not reduce cilia length, inflammation, nor O-GlcNAc levels. In contrast, Ttc21b deletion in adult ADPKD mice markedly attenuated kidney cystogenesis and reduced cilia length, inflammation, and O-GlcNAc levels. Thus, unlike IFT-B, the effect of Ttc21b deletion in mouse models of ADPKD is development-specific. Unlike an IFT-A adaptor, deleting Ttc21b in juvenile ADPKD mice is partially ameliorative. Thus, our studies suggest that different microenvironmental factors, found in distinct nephron segments and in developing versus mature stages, modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a pathological feature of ADPKD.
摘要：
初级纤毛是由滑膜内运输（IFT）多蛋白复合物建立和维持的感觉细胞器。在幼年和成人常染色体显性遗传多囊肾病(ADPKD)小鼠模型中,几个IFT-B基因的缺失减弱多囊肾病(PKD)的严重程度。然而,删除IFT-A适配器，Tulp3仅在成年小鼠中减弱PKD严重程度。这些研究表明特定纤毛成分的功能障碍具有潜在的治疗价值。为了扩大我们对纤毛功能障碍及其治疗潜力的理解，我们研究了IFT-A基因整体缺失的作用，Ttc21b,在ADPKD的青少年和成年小鼠模型中。幼年（出生后第21天）和成年（六个月大）ADPKD小鼠均表现出肾囊肿，肾脏重量/体重比增加，延长肾纤毛，炎症,增加了营养传感器的水平，O-连接的β-N-乙酰葡糖胺(O-GlcNAc)。在幼年ADPKD小鼠中缺失Ttc21b可减少皮质集合管膀胱形成和肾脏重量/体重比，近端肾小管和肾小球扩张增加，但没有减少纤毛长度，炎症,也没有O-GlcNAc水平。相比之下,成年ADPKD小鼠中的Ttc21b缺失显着减弱了肾囊形成并减少了纤毛长度，炎症,和O-GlcNAc水平。因此，与IFT-B不同,Ttc21b缺失在ADPKD小鼠模型中的作用是发育特异性的。与IFT-A适配器不同，在幼年ADPKD小鼠中删除Ttc21b是部分改善的。因此，我们的研究表明，不同的微环境因素，发现于不同的肾单位段和发育阶段与成熟阶段，改变纤毛稳态和ADPKD病理生物学。Further,O-GlcNAc水平升高，调节细胞代谢和纤毛生成，可能是ADPKD的病理特征。
