Parathyroid hormone-related protein promotes epithelial-mesenchymal transition.
Epithelial-mesenchymal transition (EMT) is an important process that contributes to renal fibrogenesis. TGF-beta1 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-beta and EGF to modulate EMT is unknown. Here, PTHrP(1-36) increased TGF-beta1 in cultured tubuloepithelial cells and TGF-beta blockade inhibited PTHrP-induced EMT-related changes, including upregulation of alpha-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-beta1 and VEGF by PTHrP(1-36). Moreover, inhibition of ERK1/2 blocked EMT induced by either PTHrP(1-36), TGF-beta1, EGF, or VEGF. In vivo, obstruction of mouse kidneys led to changes consistent with EMT and upregulation of TGF-beta1 mRNA, p-EGFR protein, and PTHrP. Taken together, these data suggest that PTHrP, TGF-beta, EGF, and VEGF might cooperate through activation of ERK1/2 to induce EMT in renal tubuloepithelial cells.
Ardura
Juan Antonio
JA
Laboratorio de Metabolismo Mineral y Oseo, Fundación Jiménez Díaz-UTE, Avda. Reyes Católicos 2, 28040 Madrid, Spain.
Rayego-Mateos
Sandra
S
Rámila
David
D
Ruiz-Ortega
Marta
M
Esbrit
Pedro
P
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000378:metabolism; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; C079957:parathyroid hormone-related peptide (1-36); D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3