Cobalt Promotes Angiogenesis via Hypoxia-Inducible Factor and Protects Tubulointerstitium in the Remnant Kidney Model

Lab Invest. 2005 Oct;85(10):1292-307. doi: 10.1038/labinvest.3700328.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Capillaries / drug effects
  • Capillaries / pathology
  • Capillary Permeability
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cobalt / pharmacology*
  • Cobalt / therapeutic use
  • Disease Models, Animal
  • Endothelial Cells / drug effects
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Female
  • Hypoxia / drug therapy*
  • Hypoxia / pathology
  • Hypoxia / physiopathology
  • Hypoxia-Inducible Factor 1 / metabolism*
  • In Situ Nick-End Labeling
  • Kidney / blood supply
  • Kidney / drug effects*
  • Kidney / pathology
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / pathology
  • Kidney Diseases / physiopathology
  • Kidney Glomerulus / blood supply
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / pathology
  • Kidney Tubules / blood supply
  • Kidney Tubules / drug effects
  • Kidney Tubules / pathology
  • Neovascularization, Physiologic*
  • Nephrectomy
  • Rats
  • Rats, Wistar
  • Vimentin / metabolism

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hypoxia-Inducible Factor 1
  • Vimentin
  • endothelial PAS domain-containing protein 1
  • Cobalt