• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Jul 1, 1998; 102(1): 202–214.
PMCID: PMC509082

Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat.

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (19M).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Thadhani R, Pascual M, Bonventre JV. Acute renal failure. N Engl J Med. 1996 May 30;334(22):1448–1460. [PubMed]
  • Lieberthal W, Levinsky NG. Treatment of acute tubular necrosis. Semin Nephrol. 1990 Nov;10(6):571–583. [PubMed]
  • Bonventre JV. Mechanisms of ischemic acute renal failure. Kidney Int. 1993 May;43(5):1160–1178. [PubMed]
  • Conger JD, Schultz MF, Miller F, Robinette JB. Responses to hemorrhagic arterial pressure reduction in different ischemic renal failure models. Kidney Int. 1994 Aug;46(2):318–323. [PubMed]
  • Witzgall R, Brown D, Schwarz C, Bonventre JV. Localization of proliferating cell nuclear antigen, vimentin, c-Fos, and clusterin in the postischemic kidney. Evidence for a heterogenous genetic response among nephron segments, and a large pool of mitotically active and dedifferentiated cells. J Clin Invest. 1994 May;93(5):2175–2188. [PMC free article] [PubMed]
  • Brady HR, Singer GG. Acute renal failure. Lancet. 1995 Dec 9;346(8989):1533–1540. [PubMed]
  • Racusen LC. Pathology of acute renal failure: structure/function correlations. Adv Ren Replace Ther. 1997 Apr;4(2 Suppl 1):3–16. [PubMed]
  • Racusen LC, Fivush BA, Li YL, Slatnik I, Solez K. Dissociation of tubular cell detachment and tubular cell death in clinical and experimental "acute tubular necrosis". Lab Invest. 1991 Apr;64(4):546–556. [PubMed]
  • Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. [PubMed]
  • Klausner JM, Paterson IS, Goldman G, Kobzik L, Rodzen C, Lawrence R, Valeri CR, Shepro D, Hechtman HB. Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol. 1989 May;256(5 Pt 2):F794–F802. [PubMed]
  • Goligorsky MS, Lieberthal W, Racusen L, Simon EE. Integrin receptors in renal tubular epithelium: new insights into pathophysiology of acute renal failure. Am J Physiol. 1993 Jan;264(1 Pt 2):F1–F8. [PubMed]
  • Kelly KJ, Williams WW, Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):812–816. [PMC free article] [PubMed]
  • Conger J. Hemodynamic factors in acute renal failure. Adv Ren Replace Ther. 1997 Apr;4(2 Suppl 1):25–37. [PubMed]
  • Humes HD, Liu S. Cellular and molecular basis of renal repair in acute renal failure. J Lab Clin Med. 1994 Dec;124(6):749–754. [PubMed]
  • Hammerman MR, Miller SB. Therapeutic use of growth factors in renal failure. J Am Soc Nephrol. 1994 Jul;5(1):1–11. [PubMed]
  • Harris RC. Growth factors and cytokines in acute renal failure. Adv Ren Replace Ther. 1997 Apr;4(2 Suppl 1):43–53. [PubMed]
  • Humes HD, Cieslinski DA, Coimbra TM, Messana JM, Galvao C. Epidermal growth factor enhances renal tubule cell regeneration and repair and accelerates the recovery of renal function in postischemic acute renal failure. J Clin Invest. 1989 Dec;84(6):1757–1761. [PMC free article] [PubMed]
  • Miller SB, Martin DR, Kissane J, Hammerman MR. Insulin-like growth factor I accelerates recovery from ischemic acute tubular necrosis in the rat. Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):11876–11880. [PMC free article] [PubMed]
  • Urist MR. Bone: formation by autoinduction. Science. 1965 Nov 12;150(3698):893–899. [PubMed]
  • Sampath TK, Reddi AH. Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci U S A. 1981 Dec;78(12):7599–7603. [PMC free article] [PubMed]
  • Hogan BL. Bone morphogenetic proteins in development. Curr Opin Genet Dev. 1996 Aug;6(4):432–438. [PubMed]
  • Helder MN, Ozkaynak E, Sampath KT, Luyten FP, Latin V, Oppermann H, Vukicevic S. Expression pattern of osteogenic protein-1 (bone morphogenetic protein-7) in human and mouse development. J Histochem Cytochem. 1995 Oct;43(10):1035–1044. [PubMed]
  • Vukicevic S, Kopp JB, Luyten FP, Sampath TK. Induction of nephrogenic mesenchyme by osteogenic protein 1 (bone morphogenetic protein 7). Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9021–9026. [PMC free article] [PubMed]
  • Dudley AT, Lyons KM, Robertson EJ. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 1995 Nov 15;9(22):2795–2807. [PubMed]
  • Luo G, Hofmann C, Bronckers AL, Sohocki M, Bradley A, Karsenty G. BMP-7 is an inducer of nephrogenesis, and is also required for eye development and skeletal patterning. Genes Dev. 1995 Nov 15;9(22):2808–2820. [PubMed]
  • Ozkaynak E, Schnegelsberg PN, Oppermann H. Murine osteogenic protein (OP-1): high levels of mRNA in kidney. Biochem Biophys Res Commun. 1991 Aug 30;179(1):116–123. [PubMed]
  • Sampath TK, Maliakal JC, Hauschka PV, Jones WK, Sasak H, Tucker RF, White KH, Coughlin JE, Tucker MM, Pang RH, et al. Recombinant human osteogenic protein-1 (hOP-1) induces new bone formation in vivo with a specific activity comparable with natural bovine osteogenic protein and stimulates osteoblast proliferation and differentiation in vitro. J Biol Chem. 1992 Oct 5;267(28):20352–20362. [PubMed]
  • Vukicevic S, Latin V, Chen P, Batorsky R, Reddi AH, Sampath TK. Localization of osteogenic protein-1 (bone morphogenetic protein-7) during human embryonic development: high affinity binding to basement membranes. Biochem Biophys Res Commun. 1994 Jan 28;198(2):693–700. [PubMed]
  • Dattatreyamurty B, Schneyer A, Reichert LE., Jr Solubilization of functional and stable follitropin receptors from light membranes of bovine calf testis. J Biol Chem. 1986 Oct 5;261(28):13104–13113. [PubMed]
  • Vukicević S, Stavljenić A, Boll T, Cervar M, Degenhardt C, Mihaljević T, Krempien B. The influence of early parathyroidectomy on aluminum-induced rickets in growing uremic rats. Bone Miner. 1989 May;6(2):125–139. [PubMed]
  • Seiberg M, Wisniewski S, Cauwenbergh G, Shapiro SS. Trypsin-induced follicular papilla apoptosis results in delayed hair growth and pigmentation. Dev Dyn. 1997 Apr;208(4):553–564. [PubMed]
  • Matejka GL, Jennische E. IGF-I binding and IGF-I mRNA expression in the post-ischemic regenerating rat kidney. Kidney Int. 1992 Nov;42(5):1113–1123. [PubMed]
  • Price PM, Megyesi J, Saggi S, Safirstein RL. Regulation of transcription by the rat EGF gene promoter in normal and ischemic murine kidney cells. Am J Physiol. 1995 Apr;268(4 Pt 2):F664–F670. [PubMed]
  • Lefer AM, Tsao PS, Ma XL, Sampath TK. Anti-ischaemic and endothelial protective actions of recombinant human osteogenic protein (hOP-1). J Mol Cell Cardiol. 1992 Jun;24(6):585–593. [PubMed]
  • Perides G, Jensen FE, Edgecomb P, Rueger DC, Charness ME. Neuroprotective effect of human osteogenic protein-1 in a rat model of cerebral hypoxia/ischemia. Neurosci Lett. 1995 Feb 24;187(1):21–24. [PubMed]
  • Chiao H, Kohda Y, McLeroy P, Craig L, Housini I, Star RA. Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest. 1997 Mar 15;99(6):1165–1172. [PMC free article] [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links