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

Ranjan Das, Shanhua Xu, Xianglan Quan, Tuyet Thi Nguyen, In Deok Kong, Choon Hee Chung, Eun Young Lee, Seung Kuy Cha, Kyu Sang Park

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42 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
Pages (from-to)F155-F167
JournalAmerican Journal of Physiology - Renal Physiology
Volume306
Issue number2
DOIs
Publication statusPublished - 2014 Jan 15

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All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

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