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.
Vukicevic
S
S
Department of Anatomy, School of Medicine, University of Zagreb, Salata 11. slobodan.vukicevic@zg.tel.hr
Basic
V
V
Rogic
D
D
Basic
N
N
Shih
M S
MS
Shepard
A
A
Jin
D
D
Dattatreyamurty
B
B
Jones
W
W
Dorai
H
H
Ryan
S
S
Griffiths
D
D
Maliakal
J
J
Jelic
M
M
Pastorcic
M
M
Stavljenic
A
A
Sampath
T K
TK
D058186:Acute Kidney Injury / Q000188:drug therapy*; D000818:Animals; D017209:Apoptosis; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology*; D006133:Growth Substances / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007511:Ischemia / Q000188:drug therapy*; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D016212:Transforming Growth Factor beta
C525819:BMP7 protein, human; C525821:Bmp7 protein, rat; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D006133:Growth Substances; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1