Parathyroid hormone-related protein (PTHrP) interacts with vascular endothelial growth factor (VEGF) in osteoblasts. Since both PTHrP and VEGF have both pro-inflammatory and pro-fibrogenic 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 up-regulation was higher in mice overexpressing PTHrP in the proximal tubule than in control littermates. These changes were associated with higher fibronectin mRNA expression and -smooth muscle actin (-SMA) and integrin-linked kinase (ILK) immunostaining and lower apoptotic tubulointerstitial cells in the mouse obstructed kidney than in control littermates. Pre-treatment 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) -SMA and ILK protein expression and decreased E-cadherin protein levels in renal tubuloepithelial MCT and 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.