Hepatocyte growth factor induces tubulogenesis of primary renal proximal tubular epithelial cells

Abstract

Hepatocyte growth factor (HGF)-induced tubulogenesis has been demonstrated with renal epithelial cell lines grown in collagen gels but not with primary cultured renal proximal tubular epithelial cells (RPTEs). We show that HGF selectively induces proliferation and branching morphogenesis of primary cultured rat RPTEs. Additional growth factors including fibroblast growth factor (FGF)-1, epidermal growth factor (EGF), FGF-7, or insulin-like growth factor-1 (IGF-1) did not selectively induce tubulogenesis. However, when administered in combination, these factors initiated branching morphogenesis comparable to HGF alone and greatly augmented HGF-induced proliferation and branching. Microscopic analysis revealed that branching RPTEs were undergoing tubulogenesis and formed a polarized epithelium. TGF-beta1 blocked HGF- or growth factor cocktail (GFC; HGF, FGF-1, EGF, IGF-1)-induced proliferation and branching morphogenesis. Adding TGF-beta1 after GFC-induced tubulogenesis had occurred caused a progressive regression of the tubular structures, a response associated with an increase in apoptosis of the RPTEs. Primary cultured RPTEs are capable of undergoing HGF-induced tubulogenesis. Unlike cell lines, combinations of growth factors differentially augment the response.

Astragalus mongholicus ameliorates renal fibrosis by modulating HGF and TGF-β in rats with unilateral ureteral obstruction

“…These proteinases include matrix metalloproteinases/tissue inhibitors of metalloproteinases, and plasminogen activators/plasminogen activator inhibitors (Gong et al, 2003;Mizuno et al, 2000). TGF-β1 induces growth arrest and apoptosis in renal tubular cells and endothelial cells (Nowak and Schnellmann, 1996;, while HGF exhibits mitogenic, motogenic, morphogenic, and anti-apoptotic activities in these cell types (Bowes et al, 1999;Dai et al, 2004;Liu, 1999). Furthermore, the epithelial to myofibroblast transition can be induced by TGF-β1 and reversed by HGF (Blobe et al, 2000;Fan et al, 1999;.…”

Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury

“…Using this model, various factors have been discovered to be involved in branching tubulogenesis. Murine inner medullary collecting duct (IMCD)-3 cells (1,5,7,26) or rat primary tubular cells (4) are also utilized for the study of tubulogenesis. These in vitro models, in which HGF has been shown to induce tubular formation, are well defined, practical, and contribute to an understanding of the mechanism of tubulogenesis.…”

Crk Synergizes with Epidermal Growth Factor for Epithelial Invasion and Morphogenesis and Is Required for the Met Morphogenic Program

“…Whereas HGF promotes a branching morphogenic program in MDCK and primary renal proximal tubular epithelial cells, EGF and other growth factors fail to do so (2,7,21). However, treatment of primary renal proximal tubular epithelial cells with a combination of growth factors promotes a similar morphogenic response as HGF (21), suggesting that the co-coordinated activation of multiple signaling pathways must be achieved to undergo an invasive morphogenic program.…”

“…However, treatment of primary renal proximal tubular epithelial cells with a combination of growth factors promotes a similar morphogenic response as HGF (21), suggesting that the co-coordinated activation of multiple signaling pathways must be achieved to undergo an invasive morphogenic program. Hence, MDCK cells provide an experimental system to examine the signals that cooperate with EGF to promote epithelial cell dispersal and morphogenesis.…”