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

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)


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
Issue number2
Publication statusPublished - 2014 Jan 15

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology


Dive into the research topics of 'Upregulation of mitochondrial Nox4 mediates TGF-β-induced apoptosis in cultured mouse podocytes'. Together they form a unique fingerprint.

Cite this