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Tubular deficiency of von Hippel-Lindau attenuates renal disease progression in anti-GBM glomerulonephritis.

Abstract
In many kidney diseases, the original insult primarily involves the glomerulus and may then pass onto the tubulointerstitium. Several hypotheses link glomerular disease to tubular injury; perhaps the foremost hypothesis involves chronic tubular hypoxia. The reported effects of hypoxia and consecutive stabilization of hypoxia-inducible factors (HIFs), however, are controversial. Hypoxia induces interstitial fibrosis but also has beneficial effects on renal disease progression when HIF is activated pharmacologically. To analyze the impact of HIF on tubulointerstitial disease development in primary glomerular disease, transgenic von Hippel Lindau (VHL)-knockout mice were generated and null expression was induced before the onset of autoimmune IgG-mediated anti-glomerular basement membrane glomerulonephritis (GN). Tubular VHL knockout and, thus, local HIF-α stabilization increased renal production of vascular endothelial growth factor, tumor growth factor-β(1), and platelet-derived growth factor-B, resulting in augmented formation of capillaries and interstitial matrix, and conversion of fibroblasts to myofibroblasts. Within the glomerular disease, VHL knockout reduced the glomerular damage and attenuated tubulointerstitial injury. Likewise, proteinuria, plasma urea concentration, and tubulointerstitial matrix were decreased in VHL knockout with GN. These findings shown that tubular HIF-α stabilization in glomerular disease is beneficial for disease outcome. In comparison with VHL knockout alone, GN is a much stronger activator of fibrosis such that stimuli other than hypoxia may be considered important for renal disease progression.
AuthorsFranziska Theilig, Anne Kathrin Enke, Brigitte Scolari, Danny Polzin, Sebastian Bachmann, Robert Koesters
JournalThe American journal of pathology (Am J Pathol) Vol. 179 Issue 5 Pg. 2177-88 (Nov 2011) ISSN: 1525-2191 [Electronic] United States
PMID21925138 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Autoantibodies
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Proto-Oncogene Proteins c-sis
  • RNA, Messenger
  • Vascular Endothelial Growth Factor A
  • antiglomerular basement membrane antibody
  • Von Hippel-Lindau Tumor Suppressor Protein
Topics
  • Animals
  • Anti-Glomerular Basement Membrane Disease (physiopathology)
  • Autoantibodies (administration & dosage, pharmacology)
  • Capillaries (cytology)
  • Cell Proliferation
  • Disease Progression
  • Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
  • Immunohistochemistry
  • Kidney Glomerulus (blood supply)
  • Kidney Tubules, Proximal (metabolism)
  • Male
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic (physiology)
  • Proto-Oncogene Proteins c-sis (metabolism)
  • RNA, Messenger (metabolism)
  • Vascular Endothelial Growth Factor A (metabolism)
  • Von Hippel-Lindau Tumor Suppressor Protein (metabolism)
  • von Hippel-Lindau Disease (physiopathology)

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