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Parathyroid Hormone–Related Protein Promotes Epithelial–Mesenchymal Transition

Juan Antonio Ardura^*, Sandra Rayego-Mateos, David Rámila^*, Marta Ruiz-Ortega and Pedro Esbrit^*

*Bone and Mineral Metabolism Laboratory and
Cellular Biology in Renal Diseases Laboratory, Fundación Jiménez Díaz (Capio Group) and Universidad Autónoma de Madrid, Madrid, Spain

Correspondence: Dr. Pedro Esbrit, Laboratorio de Metabolismo Mineral y Óseo, Fundación Jiménez Díaz-UTE, Avda. Reyes Católicos 2, 28040 Madrid, Spain. Phone: 34-91-550-4894; Fax: 34-91-549-8075; E-mail: pesbrit{at}fjd.es

Received for publication May 1, 2009. Accepted for publication October 4, 2009.

Epithelial–mesenchymal transition (EMT) is an important process that contributes to renal fibrogenesis. TGF-β1 and EGF stimulate EMT. Recent studies suggested that parathyroid hormone–related protein (PTHrP) promotes fibrogenesis in the damaged kidney, apparently dependent on its interaction with vascular endothelial growth factor (VEGF), but whether it also interacts with TGF-β and EGF to modulate EMT is unknown. Here, PTHrP(1-36) increased TGF-β1 in cultured tubuloepithelial cells and TGF-β blockade inhibited PTHrP-induced EMT-related changes, including upregulation of -smooth muscle actin and integrin-linked kinase, nuclear translocation of Snail, and downregulation of E-cadherin and zonula occludens-1. PTHrP(1-36) also induced EGF receptor (EGFR) activation; inhibition of protein kinase C and metalloproteases abrogated this activation. Inhibition of EGFR activation abolished these EMT-related changes, the activation of ERK1/2, and upregulation of TGF-β1 and VEGF by PTHrP(1-36). Moreover, inhibition of ERK1/2 blocked EMT induced by either PTHrP(1-36), TGF-β1, EGF, or VEGF. In vivo, obstruction of mouse kidneys led to changes consistent with EMT and upregulation of TGF-β1 mRNA, p-EGFR protein, and PTHrP. Taken together, these data suggest that PTHrP, TGF-β, EGF, and VEGF might cooperate through activation of ERK1/2 to induce EMT in renal tubuloepithelial cells.

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673