title: Enhancement of in vitro human tubulogenesis by endothelial cell-derived factors: implications for in vivo tubular regeneration after injury.
abstract: Renal proximal tubular epithelium can regenerate after various insults. To examine whether the tubular repair process is regulated by surrounding peritubular capillaries, we established an in vitro human tubulogenesis model that mimics in vivo tubular regeneration after injury. In this model, HGF, a potent renotropic factor, dose dependently induced tubular structures in human renal proximal tubular epithelial cells cultured in gels. Consistent with regenerating tubular cells after injury, HGF-induced tubular structures expressed a developmental gene, Pax-2, and a mesenchymal marker, vimentin, and formed a lumen with aquaporin-1 expression. Electron microscopic analysis showed the presence of microvilli on the apical site of the lumen, suggesting that these structures are morphologically equivalent to renal tubules in vivo. When cocultured with human umbilical vein endothelial cells (HUVEC), HGF-induced tubular formation was significantly enhanced. This could not be reproduced by the addition of VEGF, basic FGF, or PDGF. Protein array revealed that HUVEC produced various matrix metalloproteinases (MMPs). The stimulatory effects of coculture with HUVEC or HUVEC-derived conditional medium were almost completely abolished by addition of the tissue inhibitor of metalloproteinase (TIMP)-1 or TIMP-2. These data suggest that endothelial cell-derived factors including MMPs play a critical role in tubulogenesis and imply a potential role of peritubular capillary endothelium as a source of factor(s) required for tubular recovery after injury.
authors.affiliation: Dept. of Medicine and Clinical Science, Gunma Univ. Graduate School of Medicine, Maebashi, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miya
authors.forename: Akito
authors.initials: A
authors.lastname: Maeshima
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Mishima
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sakurai
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ikeuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuroiwa
authors.forename: Keiju
authors.initials: K
authors.lastname: Hiromura
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Nojima
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007511:Ischemia / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000098:blood supply / Q000473:pathology / Q000502:physiology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration
chemical_list: D017228:Hepatocyte Growth Factor; D020782:Matrix Metalloproteinases