Mek在TNS1基因敲除中的过度活跃导致对囊性肾脏疾病的潜在治疗。,Cell Death & Disease

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Mek在TNS1基因敲除中的过度活跃导致对囊性肾脏疾病的潜在治疗。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-11-18 , DOI: 10.1038/s41419-019-2119-7
Zong-Ye Wu ₁ , Chun-Lung Chiu ₁ , Ethan Lo ₁ , Yuh-Ru Julie Lee ₂ , Soichiro Yamada ₃ , Su Hao Lo ₁

Affiliation

囊性肾脏疾病是多个充满液体的囊肿的逐步发展，可能严重损害肾脏功能并导致肾功能衰竭。TNS1（tensin-1）基因敲除小鼠会形成囊性肾脏，并会因肾衰竭而死亡。在这里，我们已经建立了TNS1基因敲除MDCK细胞，并应用3D培养系统来研究导致囊肿形成的机制。与野生型MDCK细胞形成单个管腔的囊肿不同，TNS1敲除囊肿包含多个管腔和上调的Mek / Erk活性。通过重新表达野生型TNS1可以挽救多管腔表型和Mek / Erk过度活跃，但TNS1突变体缺乏缺少其细胞-细胞连接定位必不可少的片段的表达。此外，Mek抑制剂治疗可将多腔恢复为单腔囊肿。在TNS1敲除小鼠肾脏中也检测到Mek / Erk过度活跃。用Mek抑制剂曲美替尼治疗可显着降低TNS1基因敲除肾脏的间质浸润，纤维化和扩张的小管水平。这些研究确立了TNS1的亚细胞定位在抑制Mek / Erk信号传导和维持内腔发生中的关键作用，并通过针对囊性肾脏疾病的Mek / Erk途径提供了潜在的治疗策略。

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Hyperactivity of Mek in TNS1 knockouts leads to potential treatments for cystic kidney diseases.

Cystic kidney disease is the progressive development of multiple fluid-filled cysts that may severely compromise kidney functions and lead to renal failure. TNS1 (tensin-1) knockout mice develop cystic kidneys and die from renal failure. Here, we have established TNS1-knockout MDCK cells and applied 3D culture system to investigate the mechanism leading to cyst formation. Unlike wild-type MDCK cells, which form cysts with a single lumen, TNS1-knockout cysts contain multiple lumens and upregulated Mek/Erk activities. The multiple lumen phenotype and Mek/Erk hyperactivities are rescued by re-expression of wild-type TNS1 but not the TNS1 mutant lacking a fragment essential for its cell-cell junction localization. Furthermore, Mek inhibitor treatments restore the multiple lumens back to single lumen cysts. Mek/Erk hyperactivities are also detected in TNS1-knockout mouse kidneys. Treatment with the Mek inhibitor trametinib significantly reduces the levels of interstitial infiltrates, fibrosis and dilated tubules in TNS1-knockout kidneys. These studies establish a critical role of subcellular localization of TNS1 in suppressing Mek/Erk signaling and maintaining lumenogenesis, and provide potential therapeutic strategies by targeting the Mek/Erk pathway for cystic kidney diseases.

更新日期：2019-11-18

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