Skip to main content
SpringerLink
Log in

The Glomerular Endothelium in Diabetic Nephropathy: Role of Heparanase

  • Chapter
  • First Online:
Diabetic Nephropathy

Abstract

The glomerular endothelium is an important key player in the development of diabetic nephropathy. Due to the great complexity and diverse functions of the endothelium and in particular its covering layer, the glycocalyx, any disruption or damage might contribute to vascular pathologies. One of the main glycosaminoglycans in the glomerular endothelial glycocalyx is heparan sulfate, which crucially contributes to barrier function, whereas heparan sulfate selectively binds growth factors, complement factors, leukocytes, cytokines, and chemokines. The endoglycosidase heparanase degrades heparan sulfate, thereby inducing pathological processes, which implies that under normal conditions heparanase activity should be under tight control. Overexpression of heparanase has been associated with glomerular diseases, such as diabetic nephropathy, and it was found that increased expression of glomerular heparanase correlates with loss of glomerular heparan sulfate. Therefore, heparanase could serve as a pharmacological target for diabetic nephropathy. Several factors that regulate heparanase expression and activity have been identified, whereas several compounds aiming to inhibit heparanase activity are currently explored.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. 2008;88(2):451–87.

    Article  CAS  PubMed  Google Scholar 

  2. Haraldsson B, Nystrom J. The glomerular endothelium: new insights on function and structure. Curr Opin Nephrol Hypertens. 2012;21(3):258–63.

    Article  CAS  PubMed  Google Scholar 

  3. Maezawa Y, Takemoto M, Yokote K. Cell biology of diabetic nephropathy: roles of endothelial cells, tubulointerstitial cells and podocytes. J Diabetes Investig. 2015;6(1):3–15.

    Article  PubMed  Google Scholar 

  4. Friden V, Oveland E, Tenstad O, Ebefors K, Nystrom J, Nilsson UA, et al. The glomerular endothelial cell coat is essential for glomerular filtration. Kidney Int. 2011;79(12):1322–30.

    Article  CAS  PubMed  Google Scholar 

  5. Takahashi T, Harris R. Role of endothelial nitric oxide synthase in diabetic nephropathy: lessons from diabetic eNOS knockout mice. J Diabetes Res. 2014;2014:590541.

    Article  Google Scholar 

  6. Xu J, Zou MH. Molecular insights and therapeutic targets for diabetic endothelial dysfunction. Circulation. 2009;120(13):1266–86.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Albrecht EW, Stegeman CA, Heeringa P, Henning RH, van Goor H. Protective role of endothelial nitric oxide synthase. J Pathol. 2003;199(1):8–17.

    Article  PubMed  Google Scholar 

  8. Li F, Wang CH, Wang JG, Thai T, Boysen G, Xu L, et al. Elevated tissue factor expression contributes to exacerbated diabetic nephropathy in mice lacking eNOS fed a high fat diet. J Thromb Haemost: JTH. 2010;8(10):2122–32.

    Article  CAS  PubMed  Google Scholar 

  9. Schott U, Solomon C, Fries D, Bentzer P. The endothelial glycocalyx and its disruption, protection and regeneration: a narrative review. Scand J Trauma Resusc Emerg Med. 2016;24:48.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Dane MJ, van den Berg BM, Lee DH, Boels MG, Tiemeier GL, Avramut MC, et al. A microscopic view on the renal endothelial glycocalyx. Am J Physiol Renal Physiol. 2015;308(9):F956–66.

    Article  CAS  PubMed  Google Scholar 

  11. Dane MJ, van den Berg BM, Avramut MC, Faas FG, van der Vlag J, Rops AL, et al. Glomerular endothelial surface layer acts as a barrier against albumin filtration. Am J Pathol. 2013;182(5):1532–40.

    Article  CAS  PubMed  Google Scholar 

  12. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch: Eur J Physiol. 2007;454(3):345–59.

    Article  CAS  Google Scholar 

  13. Jeansson M, Granqvist AB, Nyström JS, Haraldsson B. Functional and molecular alterations of the glomerular barrier in long-term diabetes in mice. Diabetologia. 2006;49(9):2200–9.

    Article  CAS  PubMed  Google Scholar 

  14. Cheng H, Harris RC. Renal endothelial dysfunction in diabetic nephropathy. Cardiovasc Hematol Disord Drug Targets. 2014;14(1):22–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Aird WC. Phenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res. 2007;100(2):174–90.

    Article  CAS  PubMed  Google Scholar 

  16. Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res. 2007;100(2):158–73.

    Article  CAS  PubMed  Google Scholar 

  17. Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M. Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. Diabetes. 2007;56(8):2155–60.

    Article  CAS  PubMed  Google Scholar 

  18. Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, et al. Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int. 2012;82(9):1010–7.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Satchell SC. The glomerular endothelium emerges as a key player in diabetic nephropathy. Kidney Int. 2012;82(9):949–51.

    Article  PubMed  Google Scholar 

  20. Bartlett CS, Jeansson M, Quaggin SE. Vascular growth factors and glomerular disease. Annu Rev Physiol. 2016;78:437–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rabelink TJ, van den Berg BM, Garsen M, Wang G, Elkin M, van der Vlag J. Heparanase: roles in cell survival, extracellular matrix remodelling and the development of kidney disease. Nat Rev Nephrol. 2017;13(4):201–12.

    Article  CAS  PubMed  Google Scholar 

  22. Garsen M, Rops AL, Rabelink TJ, Berden JH, van der Vlag J. The role of heparanase and the endothelial glycocalyx in the development of proteinuria. Nephrol Dial Transplant. 2014;29(1):49–55.

    Article  CAS  PubMed  Google Scholar 

  23. Esko JD, Selleck SB. Order out of chaos: assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem. 2002;71:435–71.

    Article  CAS  PubMed  Google Scholar 

  24. Rops AL, van der Vlag J, Lensen JF, Wijnhoven TJ, van den Heuvel LP, van Kuppevelt TH, et al. Heparan sulfate proteoglycans in glomerular inflammation. Kidney Int. 2004;65(3):768–85.

    Article  CAS  PubMed  Google Scholar 

  25. Wilson JC, Laloo AE, Singh S, Ferro V. 1H NMR spectroscopic studies establish that heparanase is a retaining glycosidase. Biochem Biophys Res Commun. 2014;443(1):185–8.

    Article  CAS  PubMed  Google Scholar 

  26. Gingis-Velitski S, Zetser A, Kaplan V, Ben-Zaken O, Cohen E, Levy-Adam F, et al. Heparanase uptake is mediated by cell membrane heparan sulfate proteoglycans. J Biol Chem. 2004;279(42):44084–92.

    Article  CAS  PubMed  Google Scholar 

  27. Levy-Adam F, Feld S, Cohen-Kaplan V, Shteingauz A, Gross M, Arvatz G, et al. Heparanase 2 interacts with heparan sulfate with high affinity and inhibits heparanase activity. J Biol Chem. 2010;285(36):28010–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Garsen M, Sonneveld R, Rops AL, Huntink S, van Kuppevelt TH, Rabelink TJ, et al. Vitamin D attenuates proteinuria by inhibition of heparanase expression in the podocyte. J Pathol. 2015;237(4):472–81.

    Article  CAS  PubMed  Google Scholar 

  29. van den Hoven MJ, Rops AL, Vlodavsky I, Levidiotis V, Berden JH, van der Vlag J. Heparanase in glomerular diseases. Kidney Int. 2007;72(5):543–8.

    Article  PubMed  Google Scholar 

  30. Goldberg S, Harvey SJ, Cunningham J, Tryggvason K, Miner JH. Glomerular filtration is normal in the absence of both agrin and perlecan-heparan sulfate from the glomerular basement membrane. Nephrol Dial Transplant. 2009;24(7):2044–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Harvey SJ, Jarad G, Cunningham J, Rops AL, van der Vlag J, Berden JH, et al. Disruption of glomerular basement membrane charge through podocyte-specific mutation of agrin does not alter glomerular permselectivity. Am J Pathol. 2007;171(1):139–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rops AL, Gotte M, Baselmans MH, van den Hoven MJ, Steenbergen EJ, Lensen JF, et al. Syndecan-1 deficiency aggravates anti-glomerular basement membrane nephritis. Kidney Int. 2007;72(10):1204–15.

    Article  CAS  PubMed  Google Scholar 

  33. Chen S, Wassenhove-McCarthy DJ, Yamaguchi Y, Holzman LB, van Kuppevelt TH, Jenniskens GJ, et al. Loss of heparan sulfate glycosaminoglycan assembly in podocytes does not lead to proteinuria. Kidney Int. 2008;74(3):289–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. van den Hoven MJ, Wijnhoven TJ, Li JP, Zcharia E, Dijkman HB, Wismans RG, et al. Reduction of anionic sites in the glomerular basement membrane by heparanase does not lead to proteinuria. Kidney Int. 2008;73(3):278–87.

    Article  PubMed  Google Scholar 

  35. Massena S, Christoffersson G, Hjertstrom E, Zcharia E, Vlodavsky I, Ausmees N, et al. A chemotactic gradient sequestered on endothelial heparan sulfate induces directional intraluminal crawling of neutrophils. Blood. 2010;116(11):1924–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sanderson RD, Elkin M, Rapraeger AC, Ilan N, Vlodavsky I. Heparanase regulation of cancer, autophagy and inflammation: new mechanisms and targets for therapy. FEBS J. 2017;284(1):42–55.

    Article  CAS  PubMed  Google Scholar 

  37. Abboud-Jarrous G, Atzmon R, Peretz T, Palermo C, Gadea BB, Joyce JA, et al. Cathepsin L is responsible for processing and activation of proheparanase through multiple cleavages of a linker segment. J Biol Chem. 2008;283(26):18167–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shteingauz A, Ilan N, Vlodavsky I. Processing of heparanase is mediated by syndecan-1 cytoplasmic domain and involves syntenin and alpha-actinin. Cell Mol Life Sci: CMLS. 2014;71(22):4457–70.

    Article  CAS  PubMed  Google Scholar 

  39. Wang F, Wang Y, Zhang D, Puthanveetil P, Johnson JD, Rodrigues B. Fatty acid-induced nuclear translocation of heparanase uncouples glucose metabolism in endothelial cells. Arterioscler Thromb Vasc Biol. 2012;32(2):406–14.

    Article  PubMed  Google Scholar 

  40. Buczek-Thomas JA, Hsia E, Rich CB, Foster JA, Nugent MA. Inhibition of histone acetyltransferase by glycosaminoglycans. J Cell Biochem. 2008;105(1):108–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Sasaki N, Higashi N, Taka T, Nakajima M, Irimura T. Cell surface localization of heparanase on macrophages regulates degradation of extracellular matrix heparan sulfate. J Immunol. 2004;172(6):3830–5.

    Article  CAS  PubMed  Google Scholar 

  42. Goldberg R, Rubinstein AM, Gil N, Hermano E, Li JP, van der Vlag J, et al. Role of heparanase-driven inflammatory cascade in pathogenesis of diabetic nephropathy. Diabetes. 2014;63(12):4302–13.

    Article  CAS  PubMed  Google Scholar 

  43. van den Hoven MJ, Rops AL, Bakker MA, Aten J, Rutjes N, Roestenberg P, et al. Increased expression of heparanase in overt diabetic nephropathy. Kidney Int. 2006;70(12):2100–8.

    Article  PubMed  Google Scholar 

  44. Simeonovic CJ, Ziolkowski AF, Wu Z, Choong FJ, Freeman C, Parish CR. Heparanase and autoimmune diabetes. Front Immunol. 2013;4:471.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Lygizos MI, Yang Y, Altmann CJ, Okamura K, Hernando AA, Perez MJ, et al. Heparanase mediates renal dysfunction during early sepsis in mice. Physiol Rep. 2013;1(6):e00153.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ziolkowski AF, Popp SK, Freeman C, Parish CR, Simeonovic CJ. Heparan sulfate and heparanase play key roles in mouse beta cell survival and autoimmune diabetes. J Clin Invest. 2012;122(1):132–41.

    Article  CAS  PubMed  Google Scholar 

  47. Gil N, Goldberg R, Neuman T, Garsen M, Zcharia E, Rubinstein AM, et al. Heparanase is essential for the development of diabetic nephropathy in mice. Diabetes. 2012;61(1):208–16.

    Article  CAS  PubMed  Google Scholar 

  48. Singh A, Ramnath RD, Foster RR, Wylie EC, Friden V, Dasgupta I, et al. Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx. PLoS One. 2013;8(2):e55852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. van den Hoven MJ, Waanders F, Rops AL, Kramer AB, van Goor H, Berden JH, et al. Regulation of glomerular heparanase expression by aldosterone, angiotensin II and reactive oxygen species. Nephrol Dial Transplant. 2009;24(9):2637–45.

    Article  PubMed  Google Scholar 

  50. Garsen M, Lenoir O, Rops AL, Dijkman HB, Willemsen B, van Kuppevelt TH, et al. Endothelin-1 induces proteinuria by heparanase-mediated disruption of the glomerular glycocalyx. J Am Soc Nephrol: JASN. 2016;27(12):3545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tashiro K, Koyanagi I, Saitoh A, Shimizu A, Shike T, Ishiguro C, et al. Urinary levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and renal injuries in patients with type 2 diabetic nephropathy. J Clin Lab Anal. 2002;16(1):1–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Garsen M, Rops AL, Dijkman H, Willemsen B, van Kuppevelt TH, Russel FG, et al. Cathepsin L is crucial for the development of early experimental diabetic nephropathy. Kidney Int. 2016;90(5):1012–22.

    Article  CAS  PubMed  Google Scholar 

  53. Lerner I, Hermano E, Zcharia E, Rodkin D, Bulvik R, Doviner V, et al. Heparanase powers a chronic inflammatory circuit that promotes colitis-associated tumorigenesis in mice. J Clin Invest. 2011;121(5):1709–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Blich M, Golan A, Arvatz G, Sebbag A, Shafat I, Sabo E, et al. Macrophage activation by heparanase is mediated by TLR-2 and TLR-4 and associates with plaque progression. Arterioscler Thromb Vasc Biol. 2013;33(2):e56–65.

    Article  CAS  PubMed  Google Scholar 

  55. Goodall KJ, Poon IKH, Phipps S, Hulett MD. Soluble heparan sulfate fragments generated by heparanase trigger the release of pro-inflammatory cytokines through TLR-4. PLoS One. 2014;9(10):e109596.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Goldberg R, Sonnenblick A, Hermano E, Hamburger T, Meirovitz A, Peretz T, et al. Heparanase augments insulin receptor signaling in breast carcinoma. Oncotarget. 2017;8(12):19403–12.

    Article  PubMed  Google Scholar 

  57. Yaddanapudi S, Altintas MM, Kistler AD, Fernandez I, Moller CC, Wei C, et al. CD2AP in mouse and human podocytes controls a proteolytic program that regulates cytoskeletal structure and cellular survival. J Clin Invest. 2011;121(10):3965–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Sever S, Altintas MM, Nankoe SR, Moller CC, Ko D, Wei C, et al. Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest. 2007;117(8):2095–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Nakagawa T, Kosugi T, Haneda M, Rivard CJ, Long DA. Abnormal angiogenesis in diabetic nephropathy. Diabetes. 2009;58(7):1471–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest. 2001;108(3):341–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zetser A, Bashenko Y, Edovitsky E, Levy-Adam F, Vlodavsky I, Ilan N. Heparanase induces vascular endothelial growth factor expression: correlation with p38 phosphorylation levels and Src activation. Cancer Res. 2006;66(3):1455–63.

    Article  CAS  PubMed  Google Scholar 

  62. Ritchie JP, Ramani VC, Ren Y, Naggi A, Torri G, Casu B, et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res. 2011;17(6):1382–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kuhnast B, El Hadri A, Boisgard R, Hinnen F, Richard S, Caravano A, et al. Synthesis, radiolabeling with fluorine-18 and preliminary in vivo evaluation of a heparan sulphate mimetic as potent angiogenesis and heparanase inhibitor for cancer applications. Org Biomol Chem. 2016;14(6):1915–20.

    Article  CAS  PubMed  Google Scholar 

  64. Xu D, Esko JD. Demystifying heparan sulfate-protein interactions. Annu Rev Biochem. 2014;83:129–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Nadanaka S, Purunomo E, Takeda N, Tamura J, Kitagawa H. Heparan sulfate containing unsubstituted glucosamine residues: biosynthesis and heparanase-inhibitory activity. J Biol Chem. 2014;289(22):15231–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Poplawska A, Szelachowska M, Topolska J, Wysocka-Solowie B, Kinalska I. Effect of glycosaminoglycans on urinary albumin excretion in insulin-dependent diabetic patients with micro- or macroalbuminuria. Diabetes Res Clin Pract. 1997;38(2):109–14.

    Article  CAS  PubMed  Google Scholar 

  67. Weissmann M, Arvatz G, Horowitz N, Feld S, Naroditsky I, Zhang Y, et al. Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis. Proc Natl Acad Sci U S A. 2016;113(3):704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zetser A, Levy-Adam F, Kaplan V, Gingis-Velitski S, Bashenko Y, Schubert S, et al. Processing and activation of latent heparanase occurs in lysosomes. J Cell Sci. 2004;117(Pt 11):2249–58.

    Article  CAS  PubMed  Google Scholar 

  69. de Zeeuw D, Bekker P, Henkel E, Hasslacher C, Gouni-Berthold I, Mehling H, et al. The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial. Lancet Diabetes Endocrinol. 2015;3(9):687–96.

    Article  PubMed  Google Scholar 

  70. Menne J, Eulberg D, Beyer D, Baumann M, Saudek F, Valkusz Z, et al. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol Dial Transplant. 2017;32(2):307–15.

    PubMed  Google Scholar 

  71. Baricos WH, Cortez SL, Le QC, Wu LT, Shaw E, Hanada K, et al. Evidence suggesting a role for cathepsin L in an experimental model of glomerulonephritis. Arch Biochem Biophys. 1991;288(2):468–72.

    Article  CAS  PubMed  Google Scholar 

  72. Baricos WH, O’Connor SE, Cortez SL, Wu LT, Shah SV. The cysteine proteinase inhibitor, E-64, reduces proteinuria in an experimental model of glomerulonephritis. Biochem Biophys Res Commun. 1988;155(3):1318–23.

    Article  CAS  PubMed  Google Scholar 

  73. Guo C, Kaneko S, Sun Y, Huang Y, Vlodavsky I, Li X, et al. A mouse model of urofacial syndrome with dysfunctional urination. Hum Mol Genet. 2015;24(7):1991–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Nephrology (480), Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Johan van der Vlag & Baranca Buijsers

Authors
  1. Johan van der Vlag
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Baranca Buijsers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Johan van der Vlag .

Editor information

Editors and Affiliations

  1. Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Joris J. Roelofs

  2. Department of Internal Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Liffert Vogt

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

van der Vlag, J., Buijsers, B. (2019). The Glomerular Endothelium in Diabetic Nephropathy: Role of Heparanase. In: Roelofs, J., Vogt, L. (eds) Diabetic Nephropathy. Springer, Cham. https://doi.org/10.1007/978-3-319-93521-8_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-93521-8_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-93520-1

  • Online ISBN: 978-3-319-93521-8

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation