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

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

doi:10.1038/s41419-019-2119-7

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.

Highlights

Cystic kidney disease is a group of renal disorders that cause abnormal fluid-filled cysts
KO cell system, which develops into cysts with multiple lumens that mimic cystic kidney defects observed in TNS1 knockout mice
This in vitro system allows us to further identify the critical roles of a TNS1 fragment that is required for TNS1′s cell–cell junction localization, for suppression of the Mek/Erk activities, and for rescuing the multiple lumen phenotype

Summary

Introduction

Cystic kidney disease is a group of renal disorders that cause abnormal fluid-filled cysts. These diseases may be acquired from chronic renal defects or inherited due to gene mutations. The most frequent form of cystic kidney disease is the inherited polycystic kidney disease (PKD), which is a common cause of end stage renal disease (ESRD)[1]. Two common types of PKD are autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). ADPKD often results from mutations in PKD1 or PKD2 genes and patients usually develop signs and symptoms between the ages of 30 and 40. ARPKD is a rarer disease caused by mutations in the PKHD1 gene and often leads

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Conclusion