title: Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model.
abstract: Tubulointerstitial hypoxia has been implicated in a number of progressive renal diseases, and several lines of evidence indicate that the administration of angiogenic growth factors ameliorates tubulointerstitial injury. We hypothesized that induction of hypoxia-inducible factors (HIF) mediates renoprotection by their angiogenic properties. At 5-9 weeks after subtotal nephrectomy, cobalt was administered to rats to activate HIF. Histological evaluation demonstrated that the tubulointerstitial injury was significantly ameliorated in animals that received cobalt (score: 2.51+/-0.12 (cobalt) vs 3.21+/-0.24 (vehicle), P<0.05). Furthermore, animals receiving cobalt had fewer vimentin- and TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. The renoprotective effect of cobalt was associated with the preservation of peritubular capillary networks (rarefaction index: 13.7+/-0.4 (cobalt) vs 18.6+/-0.9 (vehicle), P<0.01). This improvement in capillary networks was accompanied by an increased number of proliferating (PCNA-positive) glomerular and peritubular endothelial cells. The angiogenesis produced by this method was not accompanied by an increase in vascular permeability. Furthermore, in vitro experiments clarified that HIF-1 in tubular epithelial cells promotes proliferation of endothelial cells and that HIF-2 overexpressed in renal endothelial cells mediates migration and network formation. Collectively, these findings demonstrate a renoprotective role of HIF through angiogenesis and provide a rationale for therapeutic approaches to target HIF for activation.
authors.affiliation: Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kojima
authors.forename: Takamoto
authors.initials: T
authors.lastname: Ohse
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ingelfinger
authors.forename: Stephen
authors.initials: S
authors.lastname: Adler
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D000860:Hypoxia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D007684:Kidney Tubules / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D018919:Neovascularization, Physiologic; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D014746:Vimentin / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003035:Cobalt; D051793:Hypoxia-Inducible Factor 1; D014746:Vimentin; D000099162:Endothelial PAS Domain-Containing Protein 1