Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction.
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.
Hruska
K A
KA
Renal Division, Departments of Medicine, Barnes-Jewish Hospital at Washington University, St. Louis, Missouri 63110, USA. khruska@imgate.wustl.edu
Guo
G
G
Wozniak
M
M
Martin
D
D
Miller
S
S
Liapis
H
H
Loveday
K
K
Klahr
S
S
Sampath
T K
TK
Morrissey
J
J
D000199:Actins / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy / Q000188:drug therapy / Q000473:pathology; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D048429:Cell Size / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004656:Enalapril / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000150:complications / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D016212:Transforming Growth Factor beta; D014517:Ureteral Obstruction / Q000150:complications*
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D004656:Enalapril; D003094:Collagen