Haimanti Dorai

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 protein-7) is responsible for the induction of nephrogenic mesenchyme during embryonic kidney development. Gene knock-out studies showed that OP-1 null mutant mice die of renal failure within the first day of postnatal life. In the present study, we evaluated the effect of recombinant human OP-1 for the treatment of acute renal failure after 60 min bilateral renal artery occlusion in rats. Bioavailability studies in normal rats indicate that approximately 1.4 microg OP-1/ml is available in the circulation 1 min after intravenous administration of 250 microg/kg, which then declines steadily with a half life of 30 min. About 0.5% of the administered OP-1 dose/g tissue is targeted for OP-1 receptors in the kidney. We show that OP-1 preserves kidney function, as determined by reduced blood urea nitrogen and serum creatinine, and increased survival 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. Histochemical and molecular analyses demonstrate that OP-1: (a) minimizes infarction and cell necrosis, and decreases the number of plugged tubules; (b) suppresses inflammation by downregulating the expression of intercellular adhesive molecule, and prevents the accumulation and activity of neutrophils; (c) maintains the expression of the vascular smooth muscle cell phenotype in pericellular capillaries; and (d) reduces programmed cell death during the recovery. Collectively, these data suggest that OP-1 prevents the loss of kidney function associated with ischemic injury and may provide a basis for the treatment of acute renal failure.

The role of bone morphogenetic proteins in kidney development and repair

Members of TGF-β superfamily are secreted glycoproteins and have been shown to regulate biological processes as diverse as migration, proliferation and differentiation of pluripotent progenitor cells involved in the development of several organ systems during embryogenesis and in adult tissue repair [1, 2]. The kidney has been identified as a major site of bone morphogenetic protein-7 (BMP-7) synthesis during embryonal and post-natal development [1, 3, 4]. Gene knock-out [5, 6] and in vitro experiments [4, 7] demonstrated the importance of BMP-7 in kidney development. Many developmental features are recapitulated during renal injury, and BMPs may be important in both preservation of function and resistance to injury [8, 9]. BMP-7 has a cytoprotective and anti-inflammatory effect in models of acute and chronic renal failure [8, 9].