| First Author | Das R | Year | 2014 |
| Journal | Am J Physiol Renal Physiol | Volume | 306 |
| Issue | 2 | Pages | F155-67 |
| PubMed ID | 24259511 | Mgi Jnum | J:205198 |
| Mgi Id | MGI:5544361 | Doi | 10.1152/ajprenal.00438.2013 |
| Citation | Das R, et al. (2014) Upregulation of mitochondrial Nox4 mediates TGF-beta-induced apoptosis in cultured mouse podocytes. Am J Physiol Renal Physiol 306(2):F155-67 |
| abstractText | 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-beta1-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-beta1 markedly depolarized mitochondrial membrane potential. TGF-beta1-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-beta1. 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-beta1. These results suggest that TGF-beta1-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. |
