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Fibroblast growth factor-2 increases the renal recruitment and attachment of HIV-infected mononuclear cells to renal tubular epithelial cells

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Abstract

The role of circulating growth factors in the pathogenesis of childhood HIV-1-associated nephropathy (HIVAN) is not clearly understood. In previous studies, we found a significant accumulation of fibroblast growth factor-2 (FGF-2) in the circulation and kidneys of children with HIVAN. The purpose of this study was to determine whether circulating FGF-2 may play a role in the pathogenesis of HIVAN by increasing the renal recruitment and attachment of HIV-infected mononuclear cells to renal epithelial cells. Using in vitro cell adhesion assays, we showed that FGF-2 increased the attachment of peripheral blood mononuclear cells (PBMCs) to fibronectin-coated tissue culture dishes by approximately threefold through a mechanism that involved the α5 integrin subunit. In addition, we found that FGF-2 induces a similar increase in the attachment of HIV-infected PBMCs and monocytes/macrophages to plastic tissue culture dishes and to monolayers of primary renal tubular epithelial cells harvested from the urine of HIV-infected children with renal disease. Finally, we injected 16 adult C57Bl6/J male mice with recombinant adenoviral vectors carrying either the LacZ gene or a secreted form of human FGF-2 (5×108 pfu/mouse) and demonstrated that high levels of circulating FGF-2 can increase the renal recruitment of circulating inflammatory cells and induce transient tubulointerstitial injury in vivo. These data suggest that FGF-2 may have an immunomodulatory role in the pathogenesis of HIVAN by recruiting HIV-infected cells in the kidney.

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References

  1. Rao TK, Filippone EJ, Nicastri AD, Landesman SH, Frank S, Chen CK, Friedman EA (1984) Associated focal and segmental glomerulosclerosis in the acquired immunodeficiency syndrome. N Engl J Med 310:669–673

    PubMed  Google Scholar 

  2. Pardo V, Aldana M, Colton RM, Fischl MA, Jaffe D, Moskowitz L, Hensley T, Bourgoignie JJ (1984) Glomerular lesions in the acquired immunodeficiency syndrome. Ann Intern Med 101:429–434

    PubMed  Google Scholar 

  3. Strauss J, Abitbol C, Zilleurelo G, Scott G, Paredes A, Malaga S, Montane BS, Mitchell C, Parks W, Pardo V (1989) Renal disease in children with the acquired immunodeficiency syndrome. N Engl J Med 321:625–630

    PubMed  Google Scholar 

  4. Ray PE, Rakusan T. Loechelt BJ, Selby DM, Liu XH, Chandra RS (1998) Human immunodeficiency virus (HIV)-associated nephropathy in children from the Washington D. C. area: 12 years’ experience. Semin Nephrol 18:396–405

    PubMed  Google Scholar 

  5. Lucas GM, Eustace JA, Sozio S, Mentari EK, Appiah KA, Moore RD (2004) Highly active antiretroviral therapy and incidence of HIV-1 associated nephropathy: a 12-year cohort study. AIDS 18:541–546

    Article  PubMed  Google Scholar 

  6. Szczech LA, Gupta SK, Habash R, Guasch A, Kalayjian R, Appel R, Fields TA, Svetkey LP, Flanagan KH, Klotman PE, Winston JA (2004) The clinical epidemiology and course of the spectrum of renal diseases with HIV infection. Kidney Int 66:1145–1152

    Article  PubMed  Google Scholar 

  7. Ray PE, Xu L, Rakusan T, Liu XH (2004) A 20-year history of childhood HIV-associated nephropathy. Pediatr Nephrol 19:1075–1092

    Article  PubMed  Google Scholar 

  8. Cohen AH, Sun NCJ, Shapshak P, Imagawa DT (1989) Demonstration of human immunodeficiency virus in renal epithelium in HIV-associated nephropathy. Mod Pathol 1:87–97

    Google Scholar 

  9. Winston JA, Bruggeman LA, Ross MD, Jacobson M, Ross L, D’Agati VD, Klotman PE, Klotman ME (2001) Nephropathy and establishment of a renal reservoir of HIV type 1 during primary infection. N Engl J Med 344:1979–1984

    Article  PubMed  Google Scholar 

  10. Schwartz EJ, Cara A, Snoeck H, Ross MD, Sunamoto M, Reiser J, Mundel P, Klotman PE (2001) Human immunodeficiency virus-1 induces loss of contact inhibition in podocytes. J Am Soc Nephrol 12:1677–1684

    PubMed  Google Scholar 

  11. Bruggeman LA, Dikman S, Meng C, Quaggin SE, Coffman TM, Klotman PE (1997) Nephropathy in human immunodeficiency virus-1 transgenic mice is due to renal transgene expression. J Clin Invest 100:84–92

    PubMed  Google Scholar 

  12. Tinkle BT, Ueda H, Ngo L, Luciw PA, Shaw K, Rosen CA, Jay G (1997) Transgenic dissection of HIV-genes involved in lymphoid depletion. J Clin Invest 100:32–39

    PubMed  Google Scholar 

  13. Kopp JB, Winkler C HIV-associated nephropathy in African Americans (2003) Kidney Int Suppl 83:S43-S49

    Article  PubMed  Google Scholar 

  14. Kimmel PL, Barisoni L, Kopp JB (2003) Pathogenesis and treatment of HIV-associated renal diseases: lessons from clinical and animal studies, molecular pathologic correlations, and genetic investigation. Ann Intern Med 139:214–226

    PubMed  Google Scholar 

  15. Bussolino F, Mitola S, Serini G, Barillari G, Ensoli B (2001) Interactions between endothelial cells and HIV-1. Int J Biochem Cell Biol 33:371–390

    Article  PubMed  Google Scholar 

  16. Wolf K, Tsakiris DA, Weber R, Erb P, Battegay M, Swiss HIV Cohort Study (2002) Antiretroviral therapy reduces markers of endothelial and coagulation activation in patients infected with Human Immunodeficiency Virus Type 1. J Infect Dis 185:456–462

    Article  PubMed  Google Scholar 

  17. Zietz C, Hotz B, Sturzl M, Rauch E, Penning R, Lolhrs U (1996) Aortic endothelium in HIV-1 infection. Chronic injury, activation, and increased leukocyte adherence. Am J Pathol 149:1887–1898

    PubMed  Google Scholar 

  18. Gilles PN, Lathey JL, Spector SA (1995) Replication of macrophage-tropic and T-cell-tropic strains of Human Immunodeficiency Virus type 1 is augmented by macrophage-endothelial cell contact. J Virol 69:2133–2139

    PubMed  Google Scholar 

  19. Ray PE, Liu X-H, Xu L, Rakusan T (1999) Accumulation of bFGF in children with HIV-1 associated hemolytic uremic syndrome. Pediatr Nephrol 13:586–593

    Article  PubMed  Google Scholar 

  20. Ascherl G, Sgadari C, Bugarini R, Bogner J, Schatz O, Ensoli B, Sturzl M (2001) Serum concentrations of fibroblast growth factor 2 are increased in HIV type 1-infected patients and inversely related to survival probably. AIDS Res Hum Retrov 17:1035–1039

    Article  Google Scholar 

  21. Gospodarozwicz D, Ferrara N, Schweigerer L, Neufeld G (1987) Structural characterization and biological functions of fibroblast growth factor. Endocr Rev 8:95–114

    PubMed  Google Scholar 

  22. Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165–197

    Article  PubMed  Google Scholar 

  23. Ray PE, Bruggeman L, Weeks B, Kopp J, Bryant J., Owens J, Notkins A, Klotman PE (1994) Role of bFGF and its low affinity receptors in the pathogenesis of HIV-associated nephropathy in transgenic mice. Kidney Int 46:759–772

    PubMed  Google Scholar 

  24. Takeuchi A, Yoshizawa N, Yamamoto M, Sawasaki Y, Oda T, Senoo A, Niwa H, Fuse Y (1992) Basic fibroblast growth factor promotes proliferation of rat glomerular visceral epithelial cells in vitro. Am J Pathol 141:107–116

    PubMed  Google Scholar 

  25. Kriz W, Hahnel B, Rosener S, Elger M (1995) Long term treatment of rats with FGF-2 results in focal segmental glomerulosclerosis. Kidney Int 48:1435–1450

    PubMed  Google Scholar 

  26. Floege J, Eng E, Linder V, Alpers CE, Young BA, Reidy MA, Johnson RJ (1992) Rat glomerular mesangial cells synthesize basic fibroblast growth factor. Release, upregulated synthesis and mitogenicity in mesangial proliferative glomerulonephritis. J Clin Invest 90:2362–2369

    PubMed  Google Scholar 

  27. Liu X-H, Achim A, Xu L, Wellstein A, Ray PE (2001) Up-regulation of a fibroblast growth factor binding protein in children with renal diseases. Kidney Int 59:1850–1858

    Article  PubMed  Google Scholar 

  28. Ray PE, Liu XH, Henry D, Dye L, Xu L, Orenstein JM, Schuztbank TE (1998). Infection of human primary renal epithelial cells with HIV-1 from children with HIV-associated nephropathy. Kidney Int 53:1217–1229

    Article  PubMed  Google Scholar 

  29. Weston CA, Weeks BS (1996) bFGF stimulates U937 cell adhesion to fibronectin and secretion of gelatinase B. Biochem Biophy Res Comm 228:318–323

    Article  Google Scholar 

  30. Akiyama SK, Yamada SS, Wen-Tien Chen, Yamada KM (1989) Analysis of fibronectin receptor function with monoclonal antibodies: Roles in cell adhesion, migration, matrix assembly, and cytoskeletal organization. J Cell Biol 109:863–875

    Article  PubMed  Google Scholar 

  31. Halaban R, Langdon R, Birchall N, Cuono C, Baird A, Scott G, MoelmannG, McGuire J (1988) Basic fibroblast growth factor from human keratinocytes is a natural mitogen for melanocytes. J Cell Biol 107:1611–1619

    Article  PubMed  Google Scholar 

  32. Gonzalez AM, Hill DJ, Logan A, Maher PA, Baird A (1990) Distribution of basic fibroblast growth factor in the 18 day rat fetus. Localization in the basement membranes of diverse tissues. J Cell Biol 110:753–765

    Article  PubMed  Google Scholar 

  33. Reilly TM, Taylor DS, Herblin WF, Thoolen MJ, Chiu AT, Watson DW, Timmermans PB (1989) Monoclonal antibodies directed against basic fibroblast growth factor which inhibit its biological activity in vitro and in vivo. Biochem Biophys Res Commun 164:736–743

    Article  PubMed  Google Scholar 

  34. Schutzbank TE, Smith J (1995) Detection of human immunodeficiency virus type 1-proviral DNA by PCR using and electrochemiluminescence-tagged probe. J Clin Microb 33:2036–2041

    Google Scholar 

  35. Kozarsky K, Grossman M, Wilson JM (1993) Adenovirus-mediated correction of the genetic defects in hepatocytes from patients with familial hypercholesterolemia. Somat Cell Mol Genet 19:449–458

    Article  PubMed  Google Scholar 

  36. Gupta AR, Dejneka NS, D’ Amato RJ, Yang Z, Syed N, Maguire AM, Bennet J (2001) Strain-dependent anterior segment neovascularization following intravitreal gene transfer of basic fibroblast growth factor (bFGF). J Gene Med 3:252–259

    Article  PubMed  Google Scholar 

  37. Ye X, Jerebtsova M, Ray PE (2000) Liver bypass significantly increases the transduction efficiency of recombinant adenoviral vectors in the lung, intestine and kidney. Human Gene Ther 11:621–627

    Article  Google Scholar 

  38. Whalen GF, Shing Y, Folkman J (1989) The fate of intravenously administered bFGF and the effect of heparin. Growth Factors 1:157–164

    PubMed  Google Scholar 

  39. Ruoslahti E (1996) Integrin signaling and matrix assembly. Tumour Biol 17:117–124

    PubMed  Google Scholar 

  40. Weeks BS, Klotman ME, Dhawan S, Kibbey M, Rappaport J, Kleinman HK, Yamada KM, Klotman PE (1991) HIV-1 infection of human T lymphocytes results in enhanced α5β1 integrin expression. J Cell Biol 114:847–853

    Article  PubMed  Google Scholar 

  41. Ensoli B, Gendelman R, Markham P, Fiorelli V, Colombini S, Raffeld M, Cafaro A, Chang H-K, Brady JN, Gallo RC (1994) Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi’s sarcoma. Nature 371:674–680

    Article  PubMed  Google Scholar 

  42. Blotnick S, Peoples GE, Freeman MR, Eberlein TJ, Klagsbrun M (1994) T lymphocytes synthesize and export heparin-binding epidermal growth factor-like growth factor and basic fibroblast growth factor, mitogens for vascular cells and fibroblast: differential production and release by CD4+ and CD8+ T cells. Proc Natl. Acad. Sci USA 91:2890–2894

    Google Scholar 

  43. Besner G, Higashiyama S, Klagsbrun M (1990) Isolation and characterization of a macrophage-derived heparin binding growth factor. Cell Regul 1:811–819

    PubMed  Google Scholar 

  44. Ku PT, D’Amore PA (1995) Regulation of basic fibroblast growth factors gene expression and protein expression following its release from sublethally injured endothelial cells. J Cell Biochem 58:328–343

    Article  PubMed  Google Scholar 

  45. Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM (1991) Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell 64:841–848

    Article  PubMed  Google Scholar 

  46. Ray PE, Liu XH, Robinson RL, ReidW, Xu L, Owens JW,Jones OD, Denaro F, Davis HG, BryantJL (2003) A novel HIV-1 transgenic rat model of childhood HIV-1 associated nephropathy. Kidney Int 63:2242–2253

    Article  PubMed  Google Scholar 

  47. Bashkin P, Doctrow S, Klagsbrun M Svahn CM, Folkman J, Vlodavsky I (1989) Basic fibroblast growth factor binds to subendothelial extracellular matrix and is released by heparitinase and heparin-like molecules. Biochemistry 28:1737–1743

    Article  PubMed  Google Scholar 

  48. Cozzolino F, Torcia M, Lucibello M, Morbidelli L, Ziche M, Platt J, Fabiani S, Stern D (1993) Interferon-alpha and interleukin 2 synergistically enhance basic fibroblast growth factor synthesis and induce release, promoting endothelial cells growth. J Clin Invest 91:2504–2512

    PubMed  Google Scholar 

  49. Sgadari C, Monini P, Barillari G, Ensoli B (2003) Use of HIV-1 protease inhibitors to block Kaposi’s sarcoma and tumor growth. Lancet 4:537–547

    Article  Google Scholar 

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Acknowledgements

This study was supported by National Institutes of Health grants RO-1 DK 49419 and RO-1 HL 55605 and by the Fundación Argentina para el Desarrollo Infantil from Buenos Aires, Argentina.

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Correspondence to Patricio E. Ray.

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Tang, P., Jerebtsova, M., Przygodzki, R. et al. Fibroblast growth factor-2 increases the renal recruitment and attachment of HIV-infected mononuclear cells to renal tubular epithelial cells. Pediatr Nephrol 20, 1708–1716 (2005). https://doi.org/10.1007/s00467-005-2018-2

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  • DOI: https://doi.org/10.1007/s00467-005-2018-2

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