Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene.

BACKGROUND Mice with a targeted disruption of the osteopontin gene through homologous recombination in embryonic stem cells have recently been generated and shown to be characterized by unaltered fertility and normal embryonic and postnatal development, including renal development, but altered osteoclastogenesis from spleen progenitors. The lack of detectable pathological manifestations in kidneys of mice with the targeted disruption of the osteopontin gene (opn -/-) makes them an excellent model for studies of pathophysiological processes that are thought to be accompanied by changes in renal osteopontin expression. It has previously been suggested that osteopontin may play an important role in the pathophysiology of acute renal failure, thus prompting this study. METHODS Wild-type and opn -/- mice were subjected to 30 minutes of renal ischemia and were studied 24 hours later. RESULTS Control opn +/+ mice showed a significant retention of blood urea nitrogen and creatinine, which is indicative of the development of ischemic acute renal dysfunction. This was accompanied by a 2.7-fold increase in the immunodetectable osteopontin compared with sham-operated control. Animals with the disrupted osteopontin gene exhibited ischemia-induced renal dysfunction, which was twice as pronounced as that observed in mice with the intact osteopontin response to stress. In addition, the structural damage to the ischemic kidneys obtained from opn -/- mice was more pronounced than that observed in similarly treated wild-type mice. This was associated with the augmented expression of inducible nitric oxide synthase and the prevalence of nitrotyrosine residues in kidneys from opn -/- mice versus wild-type counterparts. In vitro studies with proximal tubular cells subjected to hypoxia in the presence of OPN, but not OPN with deleted arginine-glycine-aspartic acid (RGD) domain, resulted in cytoprotection. CONCLUSIONS The comparative analysis of functional and morphological sequelae of acute renal ischemia in opn +/+ and opn -/- mice provides strong evidence of renoprotective action of osteopontin in acute ischemia.

[1]  C. Y. Wang,et al.  NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. , 1998, Science.

[2]  M. McKee,et al.  Mice Lacking Osteopontin Show Normal Development and Bone Structure but Display Altered Osteoclast Formation In Vitro , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[3]  R. Nemenoff,et al.  Effect of hypoxia on proximal tubules isolated from nitric oxide synthase knockout mice. , 1998, Kidney international.

[4]  N. Fausto,et al.  NF-κB Mediates αvβ3 Integrin-induced Endothelial Cell Survival , 1998, The Journal of cell biology.

[5]  B. Hogan,et al.  Altered wound healing in mice lacking a functional osteopontin gene (spp1). , 1998, The Journal of clinical investigation.

[6]  H. Kessler,et al.  Two novel probes reveal tubular and vascular Arg-Gly-Asp (RGD) binding sites in the ischemic rat kidney. , 1997, Kidney international.

[7]  R. Wüthrich,et al.  Upregulated renal tubular CD44, hyaluronan, and osteopontin in kdkd mice with interstitial nephritis. , 1997, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[8]  J. Cha,et al.  Ultrastructural localization of osteopontin in the kidney: induction by lipopolysaccharide. , 1997, Journal of the American Society of Nephrology : JASN.

[9]  K. Hruska,et al.  Metanephric osteopontin regulates nephrogenesis in vitro. , 1997, The American journal of physiology.

[10]  D. Laskin,et al.  Osteopontin inhibits nitric oxide production and cytotoxicity by activated RAW264.7 macrophages , 1996, Journal of leukocyte biology.

[11]  E. Rollo,et al.  Differential effects of osteopontin on the cytotoxic activity of macrophages from young and old mice , 1996, Immunology.

[12]  M. Detmar,et al.  Stimulation of endothelial cell migration by vascular permeability factor/vascular endothelial growth factor through cooperative mechanisms involving the alphavbeta3 integrin, osteopontin, and thrombin. , 1996, The American journal of pathology.

[13]  M. Goligorsky,et al.  Antisense oligodeoxynucleotides to inducible NO synthase rescue epithelial cells from oxidative stress injury. , 1996, The American journal of physiology.

[14]  M. Goligorsky,et al.  In vivo targeting of inducible NO synthase with oligodeoxynucleotides protects rat kidney against ischemia. , 1996, The Journal of clinical investigation.

[15]  B. Padanilam,et al.  Insulin-like growth factor I-enhanced renal expression of osteopontin after acute ischemic injury in rats. , 1996, Endocrinology.

[16]  M. Glimcher,et al.  Receptor-Ligand Interaction Between CD44 and Osteopontin (Eta-1) , 1996, Science.

[17]  M. Young,et al.  Antisera and cDNA probes to human and certain animal model bone matrix noncollagenous proteins. , 1995, Acta orthopaedica Scandinavica. Supplementum.

[18]  W. Butler,et al.  Structural and Functional Domains of Osteopontin a , 1995, Annals of the New York Academy of Sciences.

[19]  S. Schwartz,et al.  Molecular and cellular biology of osteopontin Potential role in cardiovascular disease. , 1995, Trends in cardiovascular medicine.

[20]  A. Chambers,et al.  Site‐directed mutagenesis of the arginine‐glycine‐aspartic acid sequence in osteopontin destroys cell adhesion and migration functions , 1995, Journal of cellular biochemistry.

[21]  R. Castelein.  The Netherlands Orthopedic Society Utrecht, October 8, 1994 , 1995 .

[22]  H. Kessler,et al.  Cyclic RGD peptides ameliorate ischemic acute renal failure in rats. , 1994, Kidney international.

[23]  C. Alpers,et al.  Tubulointerstitial disease in glomerulonephritis. Potential role of osteopontin (uropontin). , 1994, The American journal of pathology.

[24]  A. Mukherjee,et al.  Osteopontin: its transglutaminase-catalyzed posttranslational modifications and cross-linking to fibronectin. , 1994, Journal of biochemistry.

[25]  R. Schrier,et al.  Nitric oxide: a mediator in rat tubular hypoxia/reoxygenation injury. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[26]  C. Alpers,et al.  Osteopontin expression in angiotensin II-induced tubulointerstitial nephritis. , 1994, Kidney international.

[27]  P G Anderson,et al.  Extensive nitration of protein tyrosines in human atherosclerosis detected by immunohistochemistry. , 1994, Biological chemistry Hoppe-Seyler.

[28]  A. Chambers,et al.  Recombinant GST‐human osteopontin fusion protein is functional in RGD‐dependent cell adhesion , 1994, Journal of cellular biochemistry.

[29]  S. Schwartz,et al.  Osteopontin promotes vascular cell adhesion and spreading and is chemotactic for smooth muscle cells in vitro. , 1994, Circulation research.

[30]  W. A. Bradley,et al.  Superoxide and peroxynitrite in atherosclerosis. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Laskin,et al.  Osteopontin inhibits induction of nitric oxide synthase gene expression by inflammatory mediators in mouse kidney epithelial cells. , 1994, The Journal of biological chemistry.

[32]  D. Denhardt,et al.  Osteopontin: a protein with diverse functions , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  P. Waterhouse,et al.  Heterogeneity of osteopontin expression among nephrons in mouse kidneys and enhanced expression in sclerotic glomeruli. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[34]  E. Manseau,et al.  Expression and distribution of osteopontin in human tissues: widespread association with luminal epithelial surfaces. , 1992, Molecular biology of the cell.

[35]  M. Nemir,et al.  Normal rat kidney cells secrete both phosphorylated and nonphosphorylated forms of osteopontin showing different physiological properties. , 1989, The Journal of biological chemistry.

[36]  A. Craig,et al.  Osteopontin, a transformation-associated cell adhesion phosphoprotein, is induced by 12-O-tetradecanoylphorbol 13-acetate in mouse epidermis. , 1989, The Journal of biological chemistry.