Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes

Ranjan Das, Shanhua Xu, Xianglan Quan, Tuyet Thi Nguyen, Indeok Kong, Choon Hee Chung, Eun Young Lee, Seungkuy Cha, Kyusang Park

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

Injury to podocytes leads to the onset of chronic renal diseases characterized by proteinuria. Elevated transforming growth factor (TGF)-β in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-β in immortalized mouse podocytes. Exogenous TGF-β1-induced podocyte apoptosis through caspase-3 activation, which was related to elevated ROS levels generated by selective upregulation of NADPH oxidase 4 (Nox4). In mouse podocytes, Nox4 was predominantly localized to mitochondria, and Nox4 upregulation by TGF-(J1 markedly depolarized mitochondrial membrane potential. TGF-(31-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-β(3 receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-β(31. Knockdown of either Smad2 or Smad3 prevented the increase of Nox4 expression, ROS generation, loss of mitochondrial membrane potential, and caspase-3 activation by TGF-β1. These results suggest that TGF-β1-induced mitochondrial Nox4 upregulation via the TGF-β receptor-Smad2/3 pathway is responsible for ROS production, mitochondrial dysfunction, and apoptosis, which may at least in part contribute to the development and progression of proteinuric glomer-ular diseases such as diabetic nephropathy.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume306
Issue number2
DOIs
Publication statusPublished - 2014 Jan 15

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Podocytes
NADPH Oxidase
Transforming Growth Factors
Up-Regulation
Apoptosis
Growth Factor Receptors
Mitochondrial Membrane Potential
Caspase 3
Diabetic Nephropathies
Caspases
Chronic Renal Insufficiency
Proteinuria
Small Interfering RNA
Mitochondria
Antioxidants
Kidney

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

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title = "Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes",
abstract = "Injury to podocytes leads to the onset of chronic renal diseases characterized by proteinuria. Elevated transforming growth factor (TGF)-β in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-β in immortalized mouse podocytes. Exogenous TGF-β1-induced podocyte apoptosis through caspase-3 activation, which was related to elevated ROS levels generated by selective upregulation of NADPH oxidase 4 (Nox4). In mouse podocytes, Nox4 was predominantly localized to mitochondria, and Nox4 upregulation by TGF-(J1 markedly depolarized mitochondrial membrane potential. TGF-(31-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-β(3 receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-β(31. Knockdown of either Smad2 or Smad3 prevented the increase of Nox4 expression, ROS generation, loss of mitochondrial membrane potential, and caspase-3 activation by TGF-β1. These results suggest that TGF-β1-induced mitochondrial Nox4 upregulation via the TGF-β receptor-Smad2/3 pathway is responsible for ROS production, mitochondrial dysfunction, and apoptosis, which may at least in part contribute to the development and progression of proteinuric glomer-ular diseases such as diabetic nephropathy.",
author = "Ranjan Das and Shanhua Xu and Xianglan Quan and Nguyen, {Tuyet Thi} and Indeok Kong and Chung, {Choon Hee} and Lee, {Eun Young} and Seungkuy Cha and Kyusang Park",
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Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes. / Das, Ranjan; Xu, Shanhua; Quan, Xianglan; Nguyen, Tuyet Thi; Kong, Indeok; Chung, Choon Hee; Lee, Eun Young; Cha, Seungkuy; Park, Kyusang.

In: American Journal of Physiology - Renal Physiology, Vol. 306, No. 2, 15.01.2014.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes

AU - Das, Ranjan

AU - Xu, Shanhua

AU - Quan, Xianglan

AU - Nguyen, Tuyet Thi

AU - Kong, Indeok

AU - Chung, Choon Hee

AU - Lee, Eun Young

AU - Cha, Seungkuy

AU - Park, Kyusang

PY - 2014/1/15

Y1 - 2014/1/15

N2 - Injury to podocytes leads to the onset of chronic renal diseases characterized by proteinuria. Elevated transforming growth factor (TGF)-β in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-β in immortalized mouse podocytes. Exogenous TGF-β1-induced podocyte apoptosis through caspase-3 activation, which was related to elevated ROS levels generated by selective upregulation of NADPH oxidase 4 (Nox4). In mouse podocytes, Nox4 was predominantly localized to mitochondria, and Nox4 upregulation by TGF-(J1 markedly depolarized mitochondrial membrane potential. TGF-(31-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-β(3 receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-β(31. Knockdown of either Smad2 or Smad3 prevented the increase of Nox4 expression, ROS generation, loss of mitochondrial membrane potential, and caspase-3 activation by TGF-β1. These results suggest that TGF-β1-induced mitochondrial Nox4 upregulation via the TGF-β receptor-Smad2/3 pathway is responsible for ROS production, mitochondrial dysfunction, and apoptosis, which may at least in part contribute to the development and progression of proteinuric glomer-ular diseases such as diabetic nephropathy.

AB - Injury to podocytes leads to the onset of chronic renal diseases characterized by proteinuria. Elevated transforming growth factor (TGF)-β in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-β in immortalized mouse podocytes. Exogenous TGF-β1-induced podocyte apoptosis through caspase-3 activation, which was related to elevated ROS levels generated by selective upregulation of NADPH oxidase 4 (Nox4). In mouse podocytes, Nox4 was predominantly localized to mitochondria, and Nox4 upregulation by TGF-(J1 markedly depolarized mitochondrial membrane potential. TGF-(31-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-β(3 receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-β(31. Knockdown of either Smad2 or Smad3 prevented the increase of Nox4 expression, ROS generation, loss of mitochondrial membrane potential, and caspase-3 activation by TGF-β1. These results suggest that TGF-β1-induced mitochondrial Nox4 upregulation via the TGF-β receptor-Smad2/3 pathway is responsible for ROS production, mitochondrial dysfunction, and apoptosis, which may at least in part contribute to the development and progression of proteinuric glomer-ular diseases such as diabetic nephropathy.

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SN - 1931-857X

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