Upregulation of mitochondrial Nox4 mediates TGF-beta-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)-beta in kidney tissue is associated with podocyte damage that ultimately results in apoptosis and detachment. We investigated the proapoptotic mechanism of TGF-beta in immortalized mouse podocytes. Exogenous TGF-beta(1)-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-beta(1) markedly depolarized mitochondrial membrane potential. TGF-beta(1)-induced ROS production and caspase activation were mitigated by an antioxidant, the Nox inhibitor diphenyleneiodonium, or small interfering RNA for Nox4. A TGF-beta receptor I blocker, SB-431542, completely reversed the changes triggered by TGF-beta(1). 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-beta(1). These results suggest that TGF-beta(1)-induced mitochondrial Nox4 upregulation via the TGF-beta 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 glomerular diseases such as diabetic nephropathy.
- All Author(s)
- R. Das
; S. H. Xu
; X. L. Quan
; T. T. Nguyen
; I. D. Kong
; C. H. Chung
; E. Y. Lee
; S. K. Cha
; K. S. Park
- Issued Date
- 2014
- Type
- Article
- Keyword
- podocyte; transforming growth factor-β; NADPH oxidase 4; mitochondria; apoptosis
- Publisher
- American Physiological Society
- ISSN
- 1931-857X
; 1522-1466
- Citation Title
- American journal of physiology. Renal physiology
- Citation Volume
- 306
- Citation Number
- 2
- Citation Start Page
- F155
- Citation End Page
- F167
- Language(ISO)
- eng
- DOI
- 10.1152/ajprenal.00438.2013
- URI
- http://schca-ir.schmc.ac.kr/handle/2022.oak/953
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