Mitogenic effects of EGF/TGFα and immunolocalization of cognate receptors in human fetal kidneys

Abstract

The involvement of epidermal growth factor (EGF) and homologous transforming growth factor (TGF) in human kidney development was studied by analyzing their effects on the regulation of DNA synthesis in organ culture and by localizing their cognate receptors. Both peptides significantly increased 3H-thymidine incorporation when added at 10-100 ng/ml, but not at 1-5 ng/ml. Furthermore, addition of an anti-EGF receptor antibody not only reduced the effect of exogenous EGF (100 ng/ml) on DNA synthesis but decreased basal 3H-thymidine incorporation. These results indicate that EGF/TGF alpha are both mitogenic in vitro and further suggest that human fetal kidneys release an endogenous EGF-related substance masking the effects of low amounts of growth factors added to culture medium. Radioautographic analyses show that EGF (100 ng/ml) increased DNA synthesis in poorly-differentiated cells of the nephrogenic zone, particularly in subcapsular mesenchyme and peritubular cells; although less responsive, epithelial cells in early nephric tubules represented another target of EGF action. The pattern of EGF/TGF alpha receptor expression was revealed immunohistochemically at different gestational ages and was shown to be related to the proliferation status. It was maximal in condensing nephrogenic cells, relatively high in newly-induced epithelium and cortical branches of ureteric epithelium, low in differentiating nephronic cells and nearly absent from renal stroma and medullary collecting ducts. Together, our results indicate that the EGF/TGF alpha system is directly involved in the regulation of nephrogenic cell proliferation during human metanephrogenesis and it is progressively down-regulated after conversion of mesenchyme into epithelium.

Expression of intermediate filaments, EGF and TGF-α in early human kidney development

“…However, in the later investigation of the same authors, both TGF-a mRNA and protein were equally expressed in the cells of the developing collecting system, as well as in the cells of the developing nephrons (Bernardini et al 2001). Significant immunoreactivity to both factors, especially in mitotic cells, confirmed the role of those growth factors in the early growth and intense development of all metanephric structures, as previously suggested by other authors (Chailler and Briere 1998;Bernardini et al 2001). A slight decrease in their expression characterized advanced developmental stages, and was coincidental with progression in maturation of nephrons.…”

“…A slight decrease in their expression characterized advanced developmental stages, and was coincidental with progression in maturation of nephrons. Despite differences in the results, conclusions resulting from studies provided on developing human kidneys agreed on the role of both factors in supporting proliferation, and on their progressive downregulation during nephrogenesis (Bernardini et al 1996;Chailler and Briere 1998). All important developmental processes including growth of the metanephros, branching of the ureteric bud and tubulogenesis seemed to be influenced by TGF-a (Rogers et al 1992), while for EGF was additionally suggested to inhibit cell death (Coles et al 1993).…”

“…Both the TGF-a and the EGF bind to the same EGF/TGF-a receptor (Bernardini et al 1996;Chailler and Briere 1998). TGF-a expression is detected in the mesonephros and the metanephros of the chick (Diaz-Ruiz et al 1993) and rat embryos (Bernardini et al 2001;Rogers et al 1992), as well as in the human fetal metanephros (Goodyer et al 1991).…”

“…Disturbances in the TGF-a and EGF expression might lead to reduction in kidney growth (Chailler and Briere 1998;Rogers et al 1992).…”

ADAM17 upregulation in human renal disease: a role in modulating TGF-α availability?

“…The fetal ADAM17 expression could be related to its role in the shedding of EGFR ligands. TGF-␣ is of special interest, since it is abundantly expressed in the nephrogenic blastema and ureteric bud of developing rat and human kidneys (1,6). Additionally, in vitro experiments showed that TGF-␣ (23,33), and also HB-EGF and amphiregulin (25), can regulate branching tubulogenesis.…”