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

Zong Ye Wu, Chun Lung Chiu, Ethan Lo, Yuh Ru Julie Lee, Soichiro Yamada, Su Hao Lo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number871
JournalCell Death and Disease
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2019

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ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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