National Institutes of Health, Kidney Disease Branch/National Institute of Diabetes and Digestive and Kidney Disease, Bethesda, MD, USA.
Nat Rev Nephrol. 2019 Dec;15(12):735-749. doi: 10.1038/s41581-019-0183-y. Epub 2019 Sep 5.
Autosomal dominant polycystic kidney disease (ADPKD) affects an estimated 1 in 1,000 people and slowly progresses to end-stage renal disease (ESRD) in about half of these individuals. Tolvaptan, a vasopressin 2 receptor blocker, has been approved by regulatory authorities in many countries as a therapy to slow cyst growth, but additional treatments that target dysregulated signalling pathways in cystic kidney and liver are needed. Metabolic reprogramming is a prominent feature of cystic cells and a potentially important contributor to the pathophysiology of ADPKD. A number of pathways previously implicated in the pathogenesis of the disease, such as dysregulated mTOR and primary ciliary signalling, have roles in metabolic regulation and may exert their effects through this mechanism. Some of these pathways are amenable to manipulation through dietary modifications or drug therapies. Studies suggest that polycystin-1 and polycystin-2, which are encoded by PKD1 and PKD2, respectively (the genes that are mutated in >99% of patients with ADPKD), may in part affect cellular metabolism through direct effects on mitochondrial function. Mitochondrial dysfunction could alter the redox state and cellular levels of acetyl-CoA, resulting in altered histone acetylation, gene expression, cytoskeletal architecture and response to cellular stress, and in an immunological response that further promotes cyst growth and fibrosis.
常染色体显性多囊肾病（ADPKD）影响估计每 1000 人中就有 1 人，并且在这些人中约有一半会缓慢进展为终末期肾病（ESRD）。加压素 2 型受体阻滞剂托伐普坦已被许多国家的监管机构批准用于减缓囊肿生长，但需要针对囊性肾脏和肝脏中失调信号通路的其他治疗方法。代谢重编程是囊性细胞的一个显著特征，也是 ADPKD 病理生理学的一个潜在重要因素。以前涉及疾病发病机制的许多途径，如失调的 mTOR 和原发性纤毛信号，在代谢调节中起作用，并且可能通过这种机制发挥作用。其中一些途径可以通过饮食改变或药物治疗来进行操作。研究表明，多囊蛋白-1 和多囊蛋白-2 分别由 PKD1 和 PKD2 编码（ADPKD 患者中 >99%的突变基因），可能通过直接影响线粒体功能部分影响细胞代谢。线粒体功能障碍可能会改变氧化还原状态和细胞内乙酰辅酶 A 水平，导致组蛋白乙酰化、基因表达、细胞骨架结构和对细胞应激的反应改变，并引起免疫反应，从而进一步促进囊肿生长和纤维化。
