title: tPA is a potent mitogen for renal interstitial fibroblasts: role of beta1 integrin/focal adhesion kinase signaling.
abstract: Proliferation and expansion of interstitial fibroblasts are predominant features of progressive chronic kidney diseases. However, how interstitial fibroblast proliferation is controlled remains ambiguous. Here we show that tissue-type plasminogen activator (tPA) is a potent mitogen that promotes interstitial fibroblast proliferation through a cascade of signaling events. In vitro, tPA promoted cell proliferation of rat kidney fibroblasts (NRK-49F), as assessed by cell counting, cell proliferation assay, and bromodeoxyuridine labeling. tPA also accelerated NRK-49F cell cycle progression. Fibroblast proliferation induced by tPA was associated with an increased expression of numerous proliferation-related genes, including c-fos, c-myc, proliferating cell nuclear antigen, and cyclin D1. The mitogenic effect of tPA was independent of its protease activity, but required LDL receptor-related protein 1. Interestingly, inhibition of beta1 integrin signaling prevented tPA-mediated fibroblast proliferation. tPA rapidly induced tyrosine phosphorylation of focal adhesion kinase (FAK), which led to activation of its downstream mitogen-activated protein kinase signaling. Blockade of FAK, but not integrin-linked kinase, abolished the tPA-triggered extracellular signal-regulated protein kinase 1/2 activation, proliferation-related gene induction, and fibroblast proliferation. In vivo, proliferation of interstitial myofibroblasts in tPA null mice was attenuated after obstructive injury, compared with the wild-type controls. These studies illustrate that tPA is a potent mitogen that promotes renal interstitial fibroblast proliferation through LDL receptor-related protein 1-mediated beta1 integrin and FAK signaling.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.forename: Hongmei
authors.initials: H
authors.lastname: Shen
authors.forename: Yayi
authors.initials: Y
authors.lastname: Hou
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mars
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005434:Flow Cytometry; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D007150:Immunohistochemistry; D019012:Integrin beta1 / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D005343:Fibrinolytic Agents; D019012:Integrin beta1; D034741:RNA, Small Interfering; D051416:Focal Adhesion Protein-Tyrosine Kinases; D010959:Tissue Plasminogen Activator