ZO-2 silencing induces renal hypertrophy through a cell cycle mechanism and the activation of YAP and the mTOR pathway

Author:

Domínguez-Calderón Alaide1,Ávila-Flores Antonia2,Ponce Arturo1,López-Bayghen Esther3,Calderón-Salinas José-Víctor4,Luis Reyes José1,Chávez-Munguía Bibiana5,Segovia José1,Angulo Carla3,Ramírez Leticia3,Gallego-Gutiérrez Helios1,Alarcón Lourdes1,Martín-Tapia Dolores1,Bautista-García Pablo1,González-Mariscal Lorenza1

Affiliation:

1. Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México

2. Department of Immunology and Oncology, National Center of Biotechnology/CSIC, Darwin 3 UAM, E-28049 Madrid, Spain

3. Department of Toxicology, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México

4. Department of Biochemistry, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México

5. Department of Infectomics and Molecular Pathogenesis, Center for Research and Advanced Studies (CINVESTAV), México D.F. 07360, México

Abstract

Renal compensatory hypertrophy (RCH) restores normal kidney function after disease or loss of kidney tissue and is characterized by an increase in organ size due to cell enlargement and not to cell proliferation. In MDCK renal epithelial cells, silencing of the tight junction protein zona occludens 2 (ZO-2 KD) induces cell hypertrophy by two mechanisms: prolonging the time that cells spend at the G1 phase of the cell cycle due to an increase in cyclin D1 level, and augmenting the rate of protein synthesis. The latter is triggered by the nuclear accumulation and increased transcriptional activity of Yes-associated protein (YAP), the main target of the Hippo pathway, which results in decreased expression of phosphatase and tensin homologue. This in turn increased the level of phosphatidylinositol (3,4,5)-triphosphate, which transactivates the Akt/mammalian target of rapamycin pathway, leading to activation of the kinase S6K1 and increased synthesis of proteins and cell size. In agreement, in a rat model of uninephrectomy, RCH is accompanied by decreased expression of ZO-2 and nuclear expression of YAP. Our results reveal a novel role of ZO-2 as a modulator of cell size.

Publisher

American Society for Cell Biology (ASCB)

Subject

Cell Biology,Molecular Biology

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