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 (αSMA). These phenotype changes in podocytes induced by Hcys were accompanied by enhanced superoxide (O 2∼) 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 gp 91phox (gp91-/-), an essential Nox subunit gene, hHcys-enhanced podocyte EMT and consequent glomerular injury were examined. In wildtype (gp91 +/+) mice, hHcys induced by a folate-free diet markedly enhanced expression of mesenchymal markers (FSP-1 and αSMA) 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.
Original language | English (US) |
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Pages (from-to) | 455-467 |
Number of pages | 13 |
Journal | Pflugers Archiv European Journal of Physiology |
Volume | 462 |
Issue number | 3 |
DOIs | |
State | Published - Sep 2011 |
Externally published | Yes |
Keywords
- Albumin
- Cellular response
- Differentiation
- Endstage renal disease
- Epithelial-to-mesenchymal transition
- Homocysteinemia
- Kidney
- NADPH oxidase
- Podocytes
- Renal
ASJC Scopus subject areas
- Physiology
- Clinical Biochemistry
- Physiology (medical)