The pathobiology of polycystic kidney disease from a metabolic viewpoint.,Nature Reviews Nephrology

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The pathobiology of polycystic kidney disease from a metabolic viewpoint.
Nature Reviews Nephrology ( IF 28.6 ) Pub Date : 2019-09-05 , DOI: 10.1038/s41581-019-0183-y
Luis Fernando Menezes ₁ , Gregory G Germino ₁

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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.

中文翻译：

从代谢的角度看多囊肾病的病理学。

常染色体显性多囊肾病 (ADPKD) 影响估计每 1,000 人中的 1 人，并且在这些人中约有一半缓慢进展为终末期肾病 (ESRD)。托伐普坦是一种加压素 2 受体阻滞剂，已被许多国家的监管机构批准作为减缓囊肿生长的疗法，但需要针对囊性肾脏和肝脏中失调的信号通路的其他治疗方法。代谢重编程是囊性细胞的一个突出特征，也是 ADPKD 病理生理学的潜在重要贡献者。先前与疾病发病机制有关的许多途径，例如失调的 mTOR 和初级纤毛信号传导，在代谢调节中发挥作用，并可能通过这种机制发挥作用。其中一些途径可以通过饮食调整或药物疗法进行操作。研究表明，分别由 PKD1 和 PKD2 编码的多囊蛋白 1 和多囊蛋白 2（在 >99% 的 ADPKD 患者中发生突变的基因）可能通过直接影响线粒体功能部分影响细胞代谢。线粒体功能障碍可以改变乙酰辅酶A的氧化还原状态和细胞水平，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发生改变，并导致进一步促进囊肿生长和纤维化的免疫反应。可能通过直接影响线粒体功能部分影响细胞代谢。线粒体功能障碍可以改变乙酰辅酶A的氧化还原状态和细胞水平，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发生改变，并导致进一步促进囊肿生长和纤维化的免疫反应。可能通过直接影响线粒体功能部分影响细胞代谢。线粒体功能障碍可以改变乙酰辅酶A的氧化还原状态和细胞水平，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发生改变，并导致进一步促进囊肿生长和纤维化的免疫反应。

更新日期：2019-09-06

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