Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria

Yingjian Li, Young Sun Kang, Chunsun Dai, Lawrence P. Kiss, Xiaoyan Wen, Youhua Liu

Research output: Contribution to journalArticle

240 Citations (Scopus)

Abstract

Podocyte dysfunction plays an essential role in the pathogenesis of proteinuria and glomerulosclerosis. However, the mechanism underlying podocyte dysfunction in many common forms of chronic kidney diseases remains poorly understood. Here we tested the hypothesis that podocytes may undergo epithelial-to-mesenchymal transition after injury. Conditionally immortalized mouse podocytes were incubated with transforming growth factor (TGF)-β1, a potent fibrogenic cytokine that is up-regulated in the diseased kidney. TGF-β1 suppressed the slit diaphragm-associated protein P-cadherin, zonula occludens-1, and nephrin, a change consistent with loss of the epithelial feature. Meanwhile, TGF-β1 induced the expression of the intermediate filament protein desmin and interstitial matrix components fibronectin and collagen I. Furthermore, TGF-β1 promoted the expression and secretion of matrix metalloproteinase-9 by podocytes. Functionally, TGF-β1 increased albumin permeability across podocyte monolayers, as demonstrated by a paracellular albumin influx assay. The expression of Snail, a key transcriptional factor that has been implicated in initiating epithelial-tomesenchymal transition, was induced by TGF-β1, and ectopic expression of Snail suppressed P-cadherin and nephrin in podocytes. In vivo, in addition to loss of nephrin and zonula occludens-1, mesenchymal markers such as desmin, fibroblast-specific protein-1, and matrix metalloproteinase-9 could be observed in glomerular podocytes of diabetic nephropathy. These results suggest that podocyte dedifferentiation and mesenchymal transition could be a potential pathway leading to their dysfunction, thereby playing a role in the genesis of proteinuria.

Original languageEnglish
Pages (from-to)299-308
Number of pages10
JournalAmerican Journal of Pathology
Volume172
Issue number2
DOIs
Publication statusPublished - 2008 Feb

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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