The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.
The role of DNA damage as a therapeutic target in autosomal dominant polycystic kidney disease.
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DNA 损伤作为常染色体显性多囊肾病治疗靶点的作用。
DOI：
10.1017/erm.2019.6
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发表时间：
2019
影响因子：
6.2
通讯作者：
Rangan,GopalaK
中科院分区：
文献类型：
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作者：
Zhang,JenniferQJ;Saravanabavan,Sayanthooran;Munt,Alexandra;Wong,AnnetteTY;Harris,DavidC;Harris,PeterC;Wang,Yiping;Rangan,GopalaK
常染色体显性多囊肾病 (ADPKD) 是最常见的单基因肾病，由 PKD1 (85%) 或 PKD2 (15%) 杂合种系突变引起。其特点是形成大量充满液体的肾囊肿，约 50% 的患者在 60 岁时会导致成人肾衰竭。 ADPKD 中的肾囊肿是局灶性和散发性的，由集合管主细胞的克隆增殖引起，但仅在 1-2% 的肾单位中出现，原因尚不清楚。先前的研究表明，肾囊肿的形成需要出生后进一步减少 PKD1（或 PKD2）剂量，但确切的触发因素尚不清楚。越来越多的证据表明，DNA 损伤以及 DNA 损伤反应途径的激活在纤毛病中发生了改变。本综述的目的是：(i) 分析 ADPKD 中 DNA 损伤与肾囊肿形成相关的证据； (ii) 评估用于评估 ADPKD DNA 损伤的生物标志物的优点和缺点，最后，(iii) 评估当前临床治疗对改变 ADPKD DNA 损伤的潜在影响。这些研究将探讨 DNA 损伤的重要性，并可能为 ADPKD 带来新的治疗方法。
Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1–2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.