Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Jul 1;102(1):202–214. doi: 10.1172/JCI2237

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

S Vukicevic 1, V Basic 1, D Rogic 1, N Basic 1, M S Shih 1, A Shepard 1, D Jin 1, B Dattatreyamurty 1, W Jones 1, H Dorai 1, S Ryan 1, D Griffiths 1, J Maliakal 1, M Jelic 1, M Pastorcic 1, A Stavljenic 1, T K Sampath 1
PMCID: PMC509082  PMID: 9649574

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 (19.0 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bonventre J. V. Mechanisms of ischemic acute renal failure. Kidney Int. 1993 May;43(5):1160–1178. doi: 10.1038/ki.1993.163. [DOI] [PubMed] [Google Scholar]
  2. Brady H. R., Singer G. G. Acute renal failure. Lancet. 1995 Dec 9;346(8989):1533–1540. doi: 10.1016/s0140-6736(95)92057-9. [DOI] [PubMed] [Google Scholar]
  3. Chiao H., Kohda Y., McLeroy P., Craig L., Housini I., Star R. A. Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest. 1997 Mar 15;99(6):1165–1172. doi: 10.1172/JCI119272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Conger J. D., Schultz M. F., Miller F., Robinette J. B. Responses to hemorrhagic arterial pressure reduction in different ischemic renal failure models. Kidney Int. 1994 Aug;46(2):318–323. doi: 10.1038/ki.1994.277. [DOI] [PubMed] [Google Scholar]
  5. Conger J. Hemodynamic factors in acute renal failure. Adv Ren Replace Ther. 1997 Apr;4(2 Suppl 1):25–37. [PubMed] [Google Scholar]
  6. Dattatreyamurty B., Schneyer A., Reichert L. E., 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] [Google Scholar]
  7. Dudley A. T., Lyons K. M., Robertson E. J. A requirement for bone morphogenetic protein-7 during development of the mammalian kidney and eye. Genes Dev. 1995 Nov 15;9(22):2795–2807. doi: 10.1101/gad.9.22.2795. [DOI] [PubMed] [Google Scholar]
  8. Goligorsky M. S., Lieberthal W., Racusen L., Simon E. E. 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. doi: 10.1152/ajprenal.1993.264.1.F1. [DOI] [PubMed] [Google Scholar]
  9. Hammerman M. R., Miller S. B. Therapeutic use of growth factors in renal failure. J Am Soc Nephrol. 1994 Jul;5(1):1–11. doi: 10.1681/ASN.V511. [DOI] [PubMed] [Google Scholar]
  10. Harris R. C. Growth factors and cytokines in acute renal failure. Adv Ren Replace Ther. 1997 Apr;4(2 Suppl 1):43–53. [PubMed] [Google Scholar]
  11. Helder M. N., Ozkaynak E., Sampath K. T., Luyten F. P., 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. doi: 10.1177/43.10.7560881. [DOI] [PubMed] [Google Scholar]
  12. Hogan B. L. Bone morphogenetic proteins in development. Curr Opin Genet Dev. 1996 Aug;6(4):432–438. doi: 10.1016/s0959-437x(96)80064-5. [DOI] [PubMed] [Google Scholar]
  13. Humes H. D., Cieslinski D. A., Coimbra T. M., Messana J. M., 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. doi: 10.1172/JCI114359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Humes H. D., Liu S. Cellular and molecular basis of renal repair in acute renal failure. J Lab Clin Med. 1994 Dec;124(6):749–754. [PubMed] [Google Scholar]
  15. Kelly K. J., Williams W. W., Jr, Colvin R. B., Bonventre J. V. 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. doi: 10.1073/pnas.91.2.812. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Klausner J. M., Paterson I. S., Goldman G., Kobzik L., Rodzen C., Lawrence R., Valeri C. R., Shepro D., Hechtman H. B. Postischemic renal injury is mediated by neutrophils and leukotrienes. Am J Physiol. 1989 May;256(5 Pt 2):F794–F802. doi: 10.1152/ajprenal.1989.256.5.F794. [DOI] [PubMed] [Google Scholar]
  17. Lefer A. M., Tsao P. S., Ma X. L., Sampath T. K. Anti-ischaemic and endothelial protective actions of recombinant human osteogenic protein (hOP-1). J Mol Cell Cardiol. 1992 Jun;24(6):585–593. doi: 10.1016/0022-2828(92)91043-5. [DOI] [PubMed] [Google Scholar]
  18. Lieberthal W., Levinsky N. G. Treatment of acute tubular necrosis. Semin Nephrol. 1990 Nov;10(6):571–583. [PubMed] [Google Scholar]
  19. Luo G., Hofmann C., Bronckers A. L., 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. doi: 10.1101/gad.9.22.2808. [DOI] [PubMed] [Google Scholar]
  20. Matejka G. L., 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. doi: 10.1038/ki.1992.395. [DOI] [PubMed] [Google Scholar]
  21. Miller S. B., Martin D. R., Kissane J., Hammerman M. R. 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. doi: 10.1073/pnas.89.24.11876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ozkaynak E., Schnegelsberg P. N., Oppermann H. Murine osteogenic protein (OP-1): high levels of mRNA in kidney. Biochem Biophys Res Commun. 1991 Aug 30;179(1):116–123. doi: 10.1016/0006-291x(91)91342-a. [DOI] [PubMed] [Google Scholar]
  23. Perides G., Jensen F. E., Edgecomb P., Rueger D. C., Charness M. E. Neuroprotective effect of human osteogenic protein-1 in a rat model of cerebral hypoxia/ischemia. Neurosci Lett. 1995 Feb 24;187(1):21–24. doi: 10.1016/0304-3940(95)11327-s. [DOI] [PubMed] [Google Scholar]
  24. Price P. M., Megyesi J., Saggi S., Safirstein R. L. 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. doi: 10.1152/ajprenal.1995.268.4.F664. [DOI] [PubMed] [Google Scholar]
  25. Racusen L. C., Fivush B. A., Li Y. L., 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] [Google Scholar]
  26. Racusen L. C. Pathology of acute renal failure: structure/function correlations. Adv Ren Replace Ther. 1997 Apr;4(2 Suppl 1):3–16. [PubMed] [Google Scholar]
  27. Sampath T. K., Maliakal J. C., Hauschka P. V., Jones W. K., Sasak H., Tucker R. F., White K. H., Coughlin J. E., Tucker M. M., Pang R. H. 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] [Google Scholar]
  28. Sampath T. K., Reddi A. H. 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. doi: 10.1073/pnas.78.12.7599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Seiberg M., Wisniewski S., Cauwenbergh G., Shapiro S. S. Trypsin-induced follicular papilla apoptosis results in delayed hair growth and pigmentation. Dev Dyn. 1997 Apr;208(4):553–564. doi: 10.1002/(SICI)1097-0177(199704)208:4<553::AID-AJA11>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  30. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  31. Thadhani R., Pascual M., Bonventre J. V. Acute renal failure. N Engl J Med. 1996 May 30;334(22):1448–1460. doi: 10.1056/NEJM199605303342207. [DOI] [PubMed] [Google Scholar]
  32. Urist M. R. Bone: formation by autoinduction. Science. 1965 Nov 12;150(3698):893–899. doi: 10.1126/science.150.3698.893. [DOI] [PubMed] [Google Scholar]
  33. Vukicevic S., Kopp J. B., Luyten F. P., Sampath T. K. 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. doi: 10.1073/pnas.93.17.9021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vukicevic S., Latin V., Chen P., Batorsky R., Reddi A. H., Sampath T. K. 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. doi: 10.1006/bbrc.1994.1100. [DOI] [PubMed] [Google Scholar]
  35. 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. doi: 10.1016/0169-6009(89)90045-7. [DOI] [PubMed] [Google Scholar]
  36. Witzgall R., Brown D., Schwarz C., Bonventre J. V. 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. doi: 10.1172/JCI117214. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES