Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction

Am J Physiol Renal Physiol. 2000 Jul;279(1):F130-43. doi: 10.1152/ajprenal.2000.279.1.F130.

Abstract

Unilateral ureteral obstruction (UUO) is a model of renal injury characterized by progressive tubulointerstitial fibrosis and renal damage, while relatively sparing the glomerulus and not producing hypertension or abnormalities in lipid metabolism. Tubulointerstitial fibrosis is a major component of several kidney diseases associated with the progression to end-stage renal failure. Here we report that when a critical renal developmental morphogen, osteogenic protein-1 (OP-1; 100 or 300 microg/kg body wt), is administered at the time of UUO and every other day thereafter, interstitial inflammation and fibrogenesis are prevented, leading to preservation of renal function during the first 5 days after obstruction. Compared with angiotensin-converting enzyme inhibition with enalapril treatment, OP-1 was more effective in preventing tubulointerstitial fibrosis and in preserving renal function. The mechanism of OP-1- induced renal protection was associated with prevention of tubular atrophy, an effect not shared with enalapril, and was related to preservation of tubular epithelial integrity. OP-1 blocked the stimulation of epithelial cell apoptosis produced by UUO, which promoted maintenance of tubular epithelial integrity. OP-1 preserved renal blood flow (RBF) during UUO, but enalapril also stimulated RBF. Thus OP-1 treatment inhibited tubular epithelial disruption stimulated by the renal injury of UUO, preventing tubular atrophy and diminishing the activation of tubulointerstitial inflammation and fibrosis and preserving renal function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Atrophy / drug therapy
  • Atrophy / pathology
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins / administration & dosage
  • Bone Morphogenetic Proteins / metabolism
  • Bone Morphogenetic Proteins / pharmacology
  • Bone Morphogenetic Proteins / therapeutic use*
  • Cell Size / drug effects
  • Collagen / metabolism
  • Enalapril / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fibrosis / complications*
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Immunohistochemistry
  • Inflammation / complications
  • Inflammation / drug therapy
  • Inflammation / immunology
  • Inflammation / pathology
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology*
  • Kidney / physiopathology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Rats
  • Rats, Sprague-Dawley
  • Renal Circulation / drug effects
  • Transforming Growth Factor beta*
  • Ureteral Obstruction / complications*

Substances

  • Actins
  • Angiotensin-Converting Enzyme Inhibitors
  • Bmp7 protein, rat
  • Bone Morphogenetic Protein 7
  • Bone Morphogenetic Proteins
  • Transforming Growth Factor beta
  • Enalapril
  • Collagen