Primary cilia are sensory organelles built and maintained by intraflagellar transport (IFT) multi-protein complexes. Deletion of different IFT-B genes attenuates polycystic kidney disease (PKD) severity in juvenile and adult Autosomal Dominant (AD) PKD mouse models, while 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, here we investigate the impact of global deletion of an IFT-A gene, Thm1, in juvenile and adult ADPKD mouse models. Both juvenile and adult models exhibited increased kidney weight:body weight (KW/BW) ratios, renal cysts, inflammation, lengthened renal cilia, and increased levels of the nutrient sensor, O-linked β-N-acetylglucosamine (O-GlcNAc). Thm1 deletion in juvenile ADPKD mice reduced KW/BW ratios and cortical collecting duct cystogenesis, but increased proximal tubular and glomerular dilations and did not reduce inflammation, cilia lengths, and O-GlcNAc signaling. In contrast, Thm1 deletion in adult ADPKD mice markedly attenuated renal cystogenesis, inflammation, cilia lengths, and O-GlcNAc. Thus, unlike IFT-B genes, the role of Thm1 deletion in ADPKD mouse models is development-specific. Unlike an IFT-A adaptor gene, deleting Thm1 in juvenile ADPKD mice is partially ameliorative. Our studies suggest that different microenvironmental factors found in distinct nephron segments and between developing and mature kidneys modify ciliary homeostasis and ADPKD pathobiology. Further, elevated levels of O-GlcNAc, which regulates cellular metabolism and ciliogenesis, may be a novel feature and critical regulator of certain key ADPKD pathological processes.

中文翻译：

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鞭毛内转运-A 缺陷以肾小管和成熟依赖性方式减弱 ADPKD

初级纤毛是由鞭毛内运输 (IFT) 多蛋白复合物构建和维持的感觉细胞器。在幼年和成年常染色体显性 (AD) PKD 小鼠模型中，删除不同的 IFT-B 基因会减轻多囊肾病 (PKD) 的严重程度，而删除 IFT-A 接头Tulp3 只会 减轻成年小鼠的 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。为了拓宽我们对纤毛功能障碍及其治疗潜力的理解，我们在这里研究了 IFT-A 基因Thm1 整体缺失的影响，在青少年和成人 ADPKD 小鼠模型中。青少年和成人模型均表现出增加的肾脏重量：体重 (KW/BW) 比率、肾囊肿、炎症、肾纤毛加长以及营养传感器、O-连接的 β-N-乙酰氨基葡萄糖 (O-GlcNAc) 水平增加。幼年 ADPKD 小鼠中的Thm1缺失降低了 KW/BW 比率和皮质集合管囊肿发生，但增加了近端肾小管和肾小球扩张，并没有减少炎症、纤毛长度和 O-GlcNAc 信号传导。相比之下，成年 ADPKD 小鼠中的 Thm1 缺失显着减弱了肾囊肿发生、炎症、纤毛长度和 O-GlcNAc。因此，与 IFT-B 基因不同，Thm1缺失在 ADPKD 小鼠模型中的作用是发育特异性的。与 IFT-A 衔接基因不同，删除Thm1在幼年 ADPKD 小鼠中部分改善。我们的研究表明，在不同肾单位节段以及发育和成熟肾脏之间发现的不同微环境因素会改变纤毛稳态和 ADPKD 病理生物学。此外，调节细胞代谢和纤毛发生的 O-GlcNAc 水平升高可能是某些关键 ADPKD 病理过程的新特征和关键调节剂。