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, In Deok
AU - Chung, Choon Hee
AU - Lee, Eun Young
AU - Cha, Seung Kuy
AU - Park, Kyu Sang
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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U2 - 10.1152/ajprenal.00438.2013
DO - 10.1152/ajprenal.00438.2013
M3 - Article
C2 - 24259511
AN - SCOPUS:84892616097
SN - 1931-857X
VL - 306
SP - F155-F167
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 2
ER -
