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

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.

GDNF drives rapid tubule morphogenesis in a novel 3D in vitro model for ADPKD

“…To further validate our approach and the findings from the RNA-Seq analysis of this new in vitro model, we investigated the changes in protein abundance of tensin-1, a gene significantly downregulated ( Tns1 , adjusted P =0.0000213), in human tissue. TNS1 was implicated in cystic kidney diseases by TNS1 knockout mouse models that developed small, but significant, cortical and medullary cysts, ultimately leading to death from renal failure ( Lo et al, 1997 ; Wu et al, 2019 ). More recently, TNS1 knockout MDCK cells have been observed to form multiluminal spheroids in 3D culture displaying alteration in morphology consistent with early stages of cystogenesis ( Wu et al, 2019 ).…”

“…TNS1 was implicated in cystic kidney diseases by TNS1 knockout mouse models that developed small, but significant, cortical and medullary cysts, ultimately leading to death from renal failure ( Lo et al, 1997 ; Wu et al, 2019 ). More recently, TNS1 knockout MDCK cells have been observed to form multiluminal spheroids in 3D culture displaying alteration in morphology consistent with early stages of cystogenesis ( Wu et al, 2019 ). Our results demonstrate that tensin-1 is significantly decreased in human APDKD tissue when compared to levels in normal human kidney.…”

“…TNS1 was implicated in cystic kidney diseases from TNS1 knock out mouse models that developed small, but significant cortical and medullary cysts, ultimately leading to Journal of Cell Science • Accepted manuscript death from renal failure (Lo et al, 1997, Wu et al, 2019. More recently, TNS1knockout MDCK cells form multiluminal spheroids in 3D culture displaying alteration in morphology consistent with early stages of cystogenesis (Wu et al, 2019).…”

Tensins – emerging insights into their domain functions, biological roles and disease relevance

“…The middle regions of tensins do not display any sequence similarity to each other and are not expected to share common functions. TNS1 contains ABD II, which interacts with the barbed end of actin filaments (Lo et al, 1994b), and the region spanning amino acids 882-1032 is necessary, but not sufficient, for the localization of human TNS1 to cell-cell junctions (Wu et al, 2019).…”

ROS-ERK Pathway as Dual Mediators of Cellular Injury and Autophagy-Associated Adaptive Response in Urinary Protein-Irritated Renal Tubular Epithelial Cells

“…However, the role of ERK pathway in renal injury is still controversial until now. The ERK pathway has proved to be a pathogenic factor in various disease models, such as cystic kidney diseases [ 11 ], kidney stones [ 12 ], and unilateral ureter obstruction kidneys [ 13 , 14 ]. More directly, Reich et al indicated that the ERK pathway mediates the albumin-induced toxicity of TECs [ 15 ].…”