Epithelial-to-mesenchymal transition in podocytes mediated by activation of NADPH oxidase in hyperhomocysteinemia

Chun Zhang, Min Xia, Krishna M. Boini, Cai Xia Li, Justine M. Abais, Xiao Xue Li, Laura A. Laperle, Pin Lan Li

Research output: Contribution to journalArticle

20 Scopus citations

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 languageEnglish (US)
Pages (from-to)455-467
Number of pages13
JournalPflugers Archiv European Journal of Physiology
Volume462
Issue number3
DOIs
StatePublished - Sep 1 2011

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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)

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