Renal expression of CD44 correlates with acute renal allograft rejection.

As CD44 is involved in the activation, proliferation, adhesion, and extravasation of lymphocytes, we hypothesized that CD44 could be involved in the pathogenesis of acute renal allograft rejection. Renal biopsies and plasma were collected from patients suffering an episode of acute renal allograft rejection. CD44 and its ligands, hyaluronic acid (HA) and osteopontin, were analyzed retrospectively by immunohistochemistry and, computer-aided, morphometric analysis. Soluble CD44 (sCD44) and osteopontin in the plasma were determined by enzyme-linked immunosorbent assay. During acute rejection episodes, CD44 and its ligands, HA and osteopontin, were upregulated in the renal allograft. Also, increased sCD44 plasma levels were observed, which correlated with both tubular expression of CD44 and the extent of infiltrate. No differences could be detected between the different pathologic grades of rejection. Upregulation of tubular CD44 and increased levels of circulating sCD44 may reflect a common pathogenic mechanism during acute renal rejection and could be useful markers in the diagnosis of acute renal rejection.

[1]  C. Alpers,et al.  Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. , 1999, Kidney international.

[2]  F. Gejyo,et al.  Expression of osteopontin in gentamicin-induced acute tubular necrosis and its recovery process. , 2001, Kidney international.

[3]  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.

[4]  B. Sis,et al.  Tubular CD44 expression in renal allograft biopsies. , 2004, Transplantation proceedings.

[5]  K. Rouschop,et al.  CD44 deficiency increases tubular damage but reduces renal fibrosis in obstructive nephropathy. , 2004, Journal of the American Society of Nephrology : JASN.

[6]  J. Williams,et al.  CD44 in glomerulonephritis: expression in human renal biopsies, the Thy 1.1 model, and by cultured mesangial cells. , 1996, Kidney international.

[7]  K. Fujii,et al.  Cross-linking of CD44 on rheumatoid synovial cells up-regulates VCAM-1. , 1999, Journal of immunology.

[8]  Yoshiya Tanaka,et al.  Crosslinking of CD44 on human osteoblastic cells upregulates ICAM‐1 and VCAM‐1 , 2003, FEBS letters.

[9]  J. R. de los Toyos,et al.  Lymphocyte recognition of high endothelium: antibodies to distinct epitopes of an 85-95-kD glycoprotein antigen differentially inhibit lymphocyte binding to lymph node, mucosal, or synovial endothelial cells , 1987, The Journal of cell biology.

[10]  R. Wüthrich,et al.  Enhanced tubular epithelial CD44 expression in MRL-lpr lupus nephritis. , 1996, Kidney international.

[11]  R. Wüthrich,et al.  Mechanisms of Hyaluronan-Induced Up-Regulation of ICAM-1 and VCAM-1 Expression by Murine Kidney Tubular Epithelial Cells: Hyaluronan Triggers Cell Adhesion Molecule Expression Through a Mechanism Involving Activation of Nuclear Factor-κB and Activating Protein-1 , 1998, The Journal of Immunology.

[12]  M. Sayegh,et al.  Immunomodulatory functions of low-molecular weight hyaluronate in an acute rat renal allograft rejection model. , 1999, Journal of the American Society of Nephrology : JASN.

[13]  H. Degrendele,et al.  Requirement for CD44 in activated T cell extravasation into an inflammatory site. , 1997, Science.

[14]  R. Wüthrich,et al.  Hyaluronan-induced cyclooxygenase-2 expression promotes thromboxane A2 production by renal cells. , 2001, Kidney international.

[15]  H. E. Hansen,et al.  The Banff 97 working classification of renal allograft pathology. , 1999, Kidney international.

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

[17]  E. Gherardi,et al.  Heparan Sulfate-modified CD44 Promotes Hepatocyte Growth Factor/Scatter Factor-induced Signal Transduction through the Receptor Tyrosine Kinase c-Met* , 1999, The Journal of Biological Chemistry.

[18]  S. Ricardo,et al.  Early and persistent up-regulated expression of renal cortical osteopontin in experimental hydronephrosis. , 1995, The American journal of pathology.

[19]  P. Kincade,et al.  Characterization of soluble CD44 in the circulation of mice. Levels are affected by immune activity and tumor growth. , 1994, Journal of immunology.

[20]  D. Jackson,et al.  Heparan Sulfate Proteoglycan Isoforms of the CD44 Hyaluronan Receptor Induced in Human Inflammatory Macrophages Can Function as Paracrine Regulators of Fibroblast Growth Factor Action* , 2000, The Journal of Biological Chemistry.

[21]  H. Degrendele,et al.  Activation and interaction of CD44 and hyaluronan in immunological systems , 1999, Journal of leukocyte biology.

[22]  K. Rouschop,et al.  Reciprocal functions of hepatocyte growth factor and transforming growth factor-beta1 in the progression of renal diseases: a role for CD44? , 2003, Kidney international. Supplement.

[23]  H. Saya,et al.  Proteolytic release of CD44 intracellular domain and its role in the CD44 signaling pathway , 2001, The Journal of cell biology.

[24]  R. Stern,et al.  Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Kirby,et al.  TUBULITIS AFTER RENAL TRANSPLANTATION: DEMONSTRATION OF AN ASSOCIATION BETWEEN CD103+ T CELLS, TRANSFORMING GROWTH FACTOR &bgr;1 EXPRESSION AND REJECTION GRADE 1 , 2001, Transplantation.

[26]  H. Saya,et al.  Regulated CD44 Cleavage under the Control of Protein Kinase C, Calcium Influx, and the Rho Family of Small G Proteins* , 1999, The Journal of Biological Chemistry.

[27]  E. Puré,et al.  Resolution of Lung Inflammation by CD44 , 2002, Science.

[28]  I. Stamenkovic,et al.  Induction of Apoptosis of Metastatic Mammary Carcinoma Cells In Vivo by Disruption of Tumor Cell Surface CD44 Function , 1997, The Journal of experimental medicine.

[29]  K. Rouschop,et al.  Protection against renal ischemia reperfusion injury by CD44 disruption. , 2005, Journal of the American Society of Nephrology : JASN.

[30]  A. Chambers,et al.  Reduced tolerance to acute renal ischemia in mice with a targeted disruption of the osteopontin gene. , 1999, Kidney international.

[31]  S. Florquin,et al.  CD44 expression in IgA nephropathy. , 2002, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[32]  P. Prehm.  Hyaluronate is synthesized at plasma membranes. , 1984, The Biochemical journal.

[33]  S. Sarıoğlu,et al.  Expression of CD44 and major histocompatibility complex class II antigens correlate with renal scarring in primary and systemic renal diseases. , 2001, Scandinavian journal of urology and nephrology.

[34]  L. Klareskog,et al.  The localization of hyaluronan in normal and rejected human kidneys. , 1990, Transplantation.

[35]  C. Magee,et al.  Update in renal transplantation. , 2004, Archives of internal medicine.

[36]  T. Laurent,et al.  INCREASED HYALURONAN IN ACUTELY REJECTING HUMAN KIDNEY GRAFTS , 1993, Transplantation.

[37]  M. Zöller,et al.  Down-modulation of host reactivity by anti-CD44 in skin transplantation. , 1998, Transplantation.

[38]  R. Greil,et al.  Elevated levels of soluble CD44 are associated with advanced disease and in vitro proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia. , 2004, Leukemia research.

[39]  C. Kainz,et al.  Serum CD44 splice variants in cervical cancer patients. , 1995, Cancer letters.

[40]  E. S. St. Clair,et al.  Serum levels of soluble CD44 in primary Sjögren's syndrome. , 2000, The Journal of rheumatology.

[41]  R. Wüthrich,et al.  Hyaluronan induces monocyte chemoattractant protein-1 expression in renal tubular epithelial cells. , 1998, Journal of the American Society of Nephrology : JASN.

[42]  Tadashi Yamamoto,et al.  Osteopontin expression in acute renal allograft rejection. , 2005, Kidney international.

[43]  R. Hällgren,et al.  Experimentally-induced warm renal ischemia induces cortical accumulation of hyaluronan in the kidney. , 1996, Kidney international.