Osteogenic protein-1 prevents renal fibrogenesis associated with ureteral obstruction

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.

Activin A Is a Potent Activator of Renal Interstitial Fibroblasts

“…Given that activin A does not induce the expression of basic FGF in NRK-49F cells (Yamashita et al, unpublished observation), the action of activin A may be independent of basic FGF in fibroblast activation, although it is possible that there is a cross-talk in the intracellular signaling between them. Conversely, BMP-7 is known to be an antifibrogenic factor and ameliorate renal fibrosis (19,20). Recently, BMP-7 was proved to be capable of antagonizing TGF-␤-induced TEMT in vivo and in vitro (21).…”

“…Basic FGF is also implicated in tubular epithelial-mesenchymal transdifferentiation (TEMT) (18). Conversely, bone morphogenetic protein-7 (BMP-7), an antifibrogenic factor, ameliorates glomerular and interstitial fibrosis (19,20). Recently, BMP-7 was proved to counteract TGF-␤-induced TEMT and reverse chronic renal injury (21).…”

BMP-7 Modulates Hyaluronan-Mediated Proximal Tubular Cell-Monocyte Interaction

“…Interstitial inflammation and fibrogenesis associated with unilateral ureteral obstruction (UUO) are also prevented in vivo by administration of BMP-7 at the time of UUO (21). BMP-7 promoted maintenance of tubular epithelial integrity in the same model.…”

“…Its expression in the kidney has been suggested to be decreased in response to injury (18,19). Furthermore, administration of BMP-7 in models of chronic and acute renal failure results in a reduction of renal interstitial injury (20,21). The second aim of this study was therefore to examine the effect of BMP-7 on HA generation by PTC and to determine how this affects PTC monocyte interactions.…”

Enhanced expression of bone morphogenetic protein system in aldosterone-treated mouse kidneys

“…7 Recent studies have provided evidence that BMPs, particularly BMP-7, have a key role in the pathogenesis of various renal diseases including early experimental diabetic 8 or obstructive 9 nephropathy. Among BMP ligands, BMP-7 has pivotal roles during embryogenic renal and eye development, 10 and BMP-7 expression is retained in only a few tissues in adults, most prominently in the kidney.…”