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Epithelial-to-mesenchymal transition in podocytes mediated by activation of NADPH oxidase in hyperhomocysteinemia.
- Source :
- Pflügers Archiv: European Journal of Physiology; Sep2011, Vol. 462 Issue 3, p455-467, 13p, 2 Color Photographs, 1 Chart, 6 Graphs
- Publication Year :
- 2011
-
Abstract
- The present study tested the hypothesis that hyperhomocysteinemia (hHcys) induces podocytes to undergo epithelial-to-mesenchymal transition (EMT) through the activation of NADPH oxidase (Nox). It was found that increased homocysteine (Hcys) level suppressed the expression of slit diaphragm-associated proteins, P-cadherin and zonula occludens-1 (ZO-1), in conditionally immortalized mouse podocytes, indicating the loss of their epithelial features. Meanwhile, Hcys remarkably increased the abundance of mesenchymal markers, such as fibroblast specific protein-1 (FSP-1) and α-smooth muscle actin (α-SMA). These phenotype changes in podocytes induced by Hcys were accompanied by enhanced superoxide ( $$ {\text{O}}_2^{{ \cdot - }} $$) production, which was substantially suppressed by inhibition of Nox activity. Functionally, Hcys significantly enhanced the permeability of the podocyte monolayer coupled with increased EMT, and this EMT-related increase in cell permeability could be restored by Nox inhibitors. In mice lacking gp91 (gp91), an essential Nox subunit gene, hHcys-enhanced podocyte EMT and consequent glomerular injury were examined. In wild-type (gp91) mice, hHcys induced by a folate-free diet markedly enhanced expression of mesenchymal markers (FSP-1 and α-SMA) but decreased expression of epithelial markers of podocytes in glomeruli, which were not observed in gp91 mouse glomeruli. Podocyte injury, glomerular sclerotic pathology, and marked albuminuria observed in gp91 mice with hHcys were all significantly attenuated in gp91 mice. These results suggest that hHcys induces EMT of podocytes through activation of Nox, which represents a novel mechanism of hHcys-associated podocyte injury. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00316768
- Volume :
- 462
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Pflügers Archiv: European Journal of Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 64307929
- Full Text :
- https://doi.org/10.1007/s00424-011-0981-y