Epithelial-to-mesenchymal transition in podocytes mediated by activation of NADPH oxidase in hyperhomocysteinemia |
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Authors: | Zhang Chun Xia Min Boini Krishna M Li Cai-Xia Abais Justine M Li Xiao-Xue Laperle Laura A Li Pin-Lan |
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Institution: | (1) Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, 410 N 12th Street, Richmond, VA 23298, USA;(2) Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Avenue, Wuhan, 430022, China; |
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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 (
\textO2 ·- {\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
phox
(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. |
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Keywords: | |
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