Obstructive nephropathy and renal fibrosis: The role of bone morphogenic protein-7 and hepatocyte growth factor.
BACKGROUND
The nephropathy induced by ureteral obstruction is associated with increased interstitial volume due to matrix deposition, fibroblast differentiation/proliferation, and monocyte infiltration. Recent studies indicate that transforming growth factor-beta (TGF-beta) is linked to renal fibrosis. Tumor necrosis factor (TNF-alpha) has a role in the recruitment of inflammatory cells. We found that infiltration of macrophages of the interstitium in unilateral ureteral obstruction (UUO) occurred as early as four hours after the onset of UUO.


METHODS
Recent studies indicate that a renal tubular development morphogen, bone morphogenetic protein-7 (BMP-7), is effective in preventing the tubulointerstitial nephritis in the setting of obstructive nephropathy. The mechanism of action appears to be preservation of epithelial cell phenotype, inhibition of epithelial-mesenchymal transdifferentiation, and inhibition of injury-induced epithelial cell apoptosis. Hepatocyte growth factor (HGF) also inhibited tubulointerstitial fibrosis.


RESULTS
In a treatment protocol in rats with ureteral ligation, BMP-7 restored renal function. The preservation of glomerular filtration rate (GFR) was accompanied by a significant decrease in cortical interstitial volume. In diabetic rats given BMP-7 proteinuria was normalized. In mice with ureteral obstruction, HGF suppressed the expression of TGF-beta and of platelet-derived growth factor. The onset of tubulointerstitial fibrosis was almost completely inhibited by HGF.


CONCLUSIONS
Both BMP-7 and HGF attenuate the tubulointerstitial fibrosis due to ureteral obstruction. They also increase GFR and renal plasma flow.
Klahr
Saulo
S
Washington University School of Medicine, St. Louis, Missouri, USA.
Morrissey
Jeremiah
J
D000818:Animals; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D005355:Fibrosis; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000473:pathology* / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000502:physiology*; D014517:Ureteral Obstruction / Q000473:pathology* / Q000503:physiopathology*
C525819:BMP7 protein, human; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor