OSTEOGENIC PROTEIN-1 (BONE MORPHOGENETIC PROTEIN-7) REDUCES SEVERITY OF INJURY AFTER ISCHEMIC ACUTE-RENAL-FAILURE IN RAT

We have shown that osteogenic protein-1 (OP-1) (bone morphogenetic pro tein-7) is responsible for the induction of nephrogenic mesenchyme dur ing embryonic kidney development. Gene knock-out studies showed that O P-1 null mutant mice die of renal failure within the first day of post natal life. In the present study, we evaluated the effect of recombina nt human OP-1 for the treatment of acute renal failure after 60 min bi lateral renal artery occlusion in rats. Bioavailability studies in nor mal rats indicate that similar to 1.4 mu g OP-1/ml is available in the circulation I min after intravenous administration of 250 mu g/kg, wh ich then declines steadily with a half life of 30 min, About 0.5% of t he administered OP-1 dose/g tissue is targeted for OP-1 receptors in t he kidney. We show that OP-1 preserves kidney function, as determined by reduced blood urea nitrogen and serum creatinine, and increased sur vival rate when administered 10 min before or 1 or 16 h after ischemia , and then at 24-h intervals up to 72 h after reperfusion, Histochemic al and molecular analyses demonstrate that OP-1: (a) minimizes infarct ion and cell necrosis, and decreases the number of plugged tubules; (b ) suppresses inflammation by downregulating the expression of intercel lular adhesive molecule, and prevents the accumulation and activity of neutrophils; (c) maintains the expression of the vascular smooth musc le cell phenotype in pericellular capillaries; and (d) reduces program med cell death during the recovery. Collectively, these data suggest t hat OP-1 prevents the loss of kidney function associated with ischemic injury and may provide a basis for the treatment of acute renal failu re.