Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease.
Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease.
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DOI：
10.1016/j.kint.2016.01.026
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发表时间：
2016-07
影响因子：
19.6
通讯作者：
Cebotaru V
中科院分区：
文献类型：
--
作者：
Cebotaru L;Liu Q;Yanda MK;Boinot C;Outeda P;Huso DL;Watnick T;Guggino WB;Cebotaru V
囊肿衬里上皮的异常增殖和通过囊性纤维化跨膜传导调节因子（CFTR）增加的囊内液体分泌被认为有助于常染色体显性遗传性多囊肾病（ADPKD）的囊肿生长。组蛋白去乙酰化酶6（HDAC6）的表达和活性在某些癌症和神经退行性疾病以及Pkd1突变型肾上皮细胞中增加。用特异性抑制剂抑制HDAC6活性可减缓癌症生长。在这里，我们研究了一种特异性HDAC6抑制剂tubacin对多囊肾囊肿生长的影响。用微管菌素处理可防止MDCK细胞（一种体外囊肿形成模型）中的囊肿形成。在ADPKD中，环AMP刺激细胞增殖并激活囊内CFTR介导的氯分泌。微管蛋白治疗下调环AMP水平，抑制细胞增殖，并抑制环AMP激活的CFTR氯电流在MDCK细胞。我们还发现，tubacin通过抑制囊肿衬里上皮细胞的增殖，下调环AMP水平，减少囊肿生长，并在Pkd 1条件性ADPKD小鼠模型中改善肾功能。因此，HDAC6可能在囊肿形成中发挥作用，并可能作为ADPKD的潜在治疗靶点。
Abnormal proliferation of cyst-lining epithelium and increased intra-cystic fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) are thought to contribute to cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Histone deacetylase 6 (HDAC6) expression and activity are increased in certain cancers, and neurodegenerative diseases, and in Pkd1-mutant renal epithelial cells. Inhibition of HDAC6 activity with specific inhibitors slows cancer growth. Here we studied the effect of tubacin, a specific HDAC6 inhibitor, on cyst growth in polycystic kidney disease. Treatment with tubacin prevented cyst formation in MDCK cells, an in vitro model of cystogenesis. Cyclic AMP stimulates cell proliferation and activates intra-cystic CFTR-mediated chloride secretion in ADPKD. Treatment with tubacin down-regulated cyclic AMP levels, inhibited cell proliferation, and inhibited cyclic AMP-activated CFTR chloride currents in MDCK cells. We also found that tubacin reduced cyst growth by inhibiting proliferation of cyst-lining epithelial cells, down-regulated cyclic AMP levels, and improved renal function in a Pkd1-conditional mouse model of ADPKD. Thus, HDAC6 could play a role in cyst formation and could serve as a potential therapeutic target in ADPKD.