Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2.

Smith JP, Pozzi A, Dhawan P, Singh AB, Harris RC
Am J Physiol Renal Physiol. 2009 296 (5): F957-65

PMID: 19244405 · PMCID: PMC2681361 · DOI:10.1152/ajprenal.90490.2008

Animal models of acute renal injury suggest that the epidermal growth factor receptor (EGFR) axis may have a beneficial role in the recovery from acute renal injury, but recent reports describe detrimental effects of EGFR activation in chronic renal injury. Expression of the EGFR ligand heparin-binding EGF-like growth factor (HB-EGF) increases following renal injury, but the effects of this sustained upregulation have not been well studied. Here, stable overexpression of soluble HB-EGF (sHB-EGF) in mouse inner medullary collecting duct (IMCD) cells led to marked phenotypic changes: sHB-EGF-expressing cells demonstrated a fibroblast-like morphology, did not form epithelial sheets, exhibited cytoplasmic projections, decreased expression of epithelial markers, and increased expression of fibroblast-specific protein-1. They also demonstrated anchorage-independent growth and formed tumors when injected subcutaneously into nude mice. Quantitative RT-PCR and a luciferase reporter assay suggested that sHB-EGF repressed transcription of E-cadherin, and a concomitant TGF-beta-independent upregulation of the E-cadherin repressor Snail-2 was observed. Stable downregulation of Snail-2 in sHB-EGF-overexpressing cells restored epithelial characteristics (E-cadherin and cytokeratin expression) but did not alter their anchorage-independent growth. In summary, sustained exposure to sHB-EGF induces epithelial-to-mesenchymal transition of IMCD cells, in part by upregulating the E-cadherin transcriptional repressor Snail-2.

MeSH Terms (20)

Animals Cadherins Cell Dedifferentiation Cell Line Epithelial Cells Gene Expression Gene Knockdown Techniques Heparin-binding EGF-like Growth Factor Intercellular Signaling Peptides and Proteins Kidney Medulla Kidney Tubules, Collecting Mesenchymal Stem Cells Mice Mice, Nude Snail Family Transcription Factors Solubility Transcription, Genetic Transcription Factors Transforming Growth Factor beta Up-Regulation

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