Parathyroid hormone-related protein interacts with vascular endothelial growth factor to promote fibrogenesis in the obstructed mouse kidney.
Parathyroid hormone-related protein (PTHrP) interacts with vascular endothelial growth factor (VEGF) in osteoblasts. Since both PTHrP and VEGF have both proinflammatory and profibrogenic features, we assessed here whether these factors might act in concert to promote fibrogenesis in the obstructed kidney. VEGF receptor (VEGFR)-1 was upregulated, while VEGFR-2 was downregulated (at both mRNA and protein levels) in the mouse kidney within 2-6 days after ureteral obstruction. VEGF protein levels also increased in the obstructed kidney at the latter time. Moreover, this VEGF and VEGFR-1 upregulation was higher in mice overexpressing PTHrP in the proximal tubule than in control littermates. These changes were associated with higher fibronectin mRNA expression and alpha-smooth muscle actin (alpha-SMA) and integrin-linked kinase (ILK) immunostaining and lower apoptotic tubulointerstitial cells in the mouse obstructed kidney than in control littermates. Pretreatment with a neutralizing anti-VEGF antibody reversed these responses in the obstructed kidney of both types of mice. In vitro, PTHrP-(1-36) increased (maximal 2-fold vs. basal, at 100 nM) alpha-SMA and ILK protein expression and decreased E-cadherin protein levels in renal tubuloepithelial mouse cortical tubule and normal rat kidney (NRK) 52E cells. PTHrP-(1-36) also decreased cyclosporine A- and/or osmotic stress-induced apoptosis in these cells and in renal fibroblastic NRK 49F cells. These effects elicited by PTHrP-(1-36) were associated with both VEGF and VEGFR-1 upregulation, and abolished by the anti-VEGF antibody. Collectively, these findings strongly suggest that VEGF acts as an important mediator of PTHrP to promote fibrogenesis in the obstructed kidney.
Bone and Mineral Metabolism Laboratory, Fundación Jiménez Díaz, Madrid, Spain.
Juan A
JA
Ardura
Raúl
R
Berruguete
David
D
Rámila
M Victoria
MV
Alvarez-Arroyo
Pedro
P
Esbrit
D000199:Actins / Q000378:metabolism; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099200:Scaffold Protein ILK
D000199:Actins; D000888:Antibodies, Anti-Idiotypic; D005353:Fibronectins; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099200:Scaffold Protein ILK; C079957:parathyroid hormone-related peptide (1-36)