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Accepted Manuscript
Research Article
High glucose induces Nox4 expression and podocyte apoptosis through the Smad3/ezrin/PKA pathway
Wanxu Guo, Hang Gao, Wei Pan, Panapn Yu, Guanghua Che
Biology Open 2020 : bio.055012 doi: 10.1242/bio.055012 Published 12 October 2020
Wanxu Guo
1Department of Pediatrics, Second Hospital, Jilin University, Changchun, 130041, China
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Hang Gao
2The Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
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Wei Pan
1Department of Pediatrics, Second Hospital, Jilin University, Changchun, 130041, China
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Panapn Yu
1Department of Pediatrics, Second Hospital, Jilin University, Changchun, 130041, China
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Guanghua Che
1Department of Pediatrics, Second Hospital, Jilin University, Changchun, 130041, China
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  • For correspondence: chegh@jlu.edu.cn
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Abstract

Podocyte is the major target in proteinuric kidney disease such as diabetic nephropathy. The underlying molecular mechanisms by which high glucose (HG) results in podocyte damage remain unclear. This study investigated the regulatory role of Smad3, ezrin, and protein kinase A (PKA) in NADPH oxidase (Nox4) expression, reactive oxidative species (ROS) production, and apoptosis in HG-treated podocytes. Human podocyte cell line was cultured and differentiated, then treated with 30 mM HG. Apoptosis and intracellular ROS level was assessed using TUNEL and DCF assay, respectively. Expressions of Nox4, phospho-Smad3Ser423/425, phospho-PKAThr197, and phospho-ezrinThr567 were evaluated using Western blotting. ELISA was used to quantify intracellular cAMP concentration and PKA activity. Knockdown assay was used to inhibit the expressions of Smad3, Nox4, and ezrin by lentiviral shRNA. In HG-treated podocytes, the level of phospho-Smad3Ser423/425 and phospho-ezrinThr567 was increased significantly, which was accompanied by the reduction of cAMP and phospho-PKAThr197. HG-induced apoptosis was significantly prevented by the Smad3 inhibitor SIS3 or shRNA-Smad3. In podocytes expressing shRNA-ezrin or shRNA-Nox4, apoptosis was remarkably mitigated following HG treatment. HG-induced upregulation of phospho-ezrinThr567 and downregulation of phospho-PKAThr197 was significantly prevented by SIS3, shRNA-ezrin or shRNA-Smad3. Forskolin, a PKA activator, significantly inhibited HG-mediated upregulation of Nox4 expression, ROS generation, and apoptosis. Additionally, an increase in the ROS level was prohibited in HG-treated podocytes with the knockdown of Nox4, Smad3, or ezrin. Taken together, our findings provided evidence that Smad3-mediated ezrin activation upregulates Nox4 expression and ROS production, by suppressing PKA activity, which may at least in part contribute to HG-induced podocyte apoptosis.

  • Received July 13, 2020.
  • Accepted September 28, 2020.
  • © 2020. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/4.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Podocyte apoptosis
  • High glucose
  • Nox4
  • Ezrin
  • PKA
  • Smad3

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Accepted Manuscript
Research Article
High glucose induces Nox4 expression and podocyte apoptosis through the Smad3/ezrin/PKA pathway
Wanxu Guo, Hang Gao, Wei Pan, Panapn Yu, Guanghua Che
Biology Open 2020 : bio.055012 doi: 10.1242/bio.055012 Published 12 October 2020
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Accepted Manuscript
Research Article
High glucose induces Nox4 expression and podocyte apoptosis through the Smad3/ezrin/PKA pathway
Wanxu Guo, Hang Gao, Wei Pan, Panapn Yu, Guanghua Che
Biology Open 2020 : bio.055012 doi: 10.1242/bio.055012 Published 12 October 2020

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