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Angiogenesis and hypoxia in the kidney

Nature Reviews Nephrology volume 9, pages 211–222 (2013)Cite this article

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Abstract

Loss of glomerular function associated with the presence of tubulointerstitial lesions, which are characterized by peritubular capillary loss, is a common finding in progressive renal disorders. Dysregulated expression of angiogenic factors (such as vascular endothelial growth factor [VEGF] and angiopoietins) and endogenous angiogenic inhibitors (such as thrombospondin-1, angiostatin and endostatin) underlie these conditions and negatively influence the balance between capillary formation and regression, resulting in capillary rarefaction. Recent studies have provided unequivocal evidence for a pathogenic role of tubulointerstitial hypoxia and the involvement of hypoxia-inducible transcription factors in the advanced stages of chronic kidney disease. The mainstay of potential angiogenic therapies is the application of angiogenic factors with the primary aim of ameliorating reduced oxygenation in the ischaemic tubulointerstitium. However, this strategy is strongly associated with inflammation and changes in vascular permeability. For example, supraphysiological expression of VEGF results in glomerular expansion and proteinuria, whereas VEGF blockade using neutralizing antibodies can cause hypertension and thrombotic microangiopathy. These effects highlight the importance of tight regulation of angiogenic factors and inhibitors. Novel therapeutic approaches that target vascular maturation and normalization are now being developed to protect kidneys from capillary rarefaction and hypoxic injury.

Key Points

  • Loss of peritubular capillaries is common during the advanced stages of chronic kidney disease (CKD) and is associated with dysregulated expression of angiogenic factors and angiogenic inhibitors

  • In the tubulointerstitium, the cellular hypoxia response mediated by hypoxia-inducible factor has both pathogenic and protective effects and chronic hypoxia leads to end-stage renal disease

  • Treatment with angiogenic factors, such as vascular endothelial growth factor (VEGF) and angiopoietin 1, prevent capillary rarefaction and ameliorate ischaemic tubulointerstitial injury in several animal models of CKD

  • VEGF-induced angiogenesis is associated with increased vascular permeability and local inflammation, which together with hypoxia, might aggravate tubulointerstitial injury

  • Data from clinical studies of anti-VEGF therapy suggest a pathogenic role of VEGF blockade in hypertension and thrombotic microangiopathy and highlight the potential risks of inappropriate control of angiogenic factors

  • Novel angiogenic therapies that target vascular maturation and normalization and might protect kidneys from tubulointerstitial injury are being developed

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Figure 1: Regulation of angiogenesis.
Figure 2: Rarefaction of the peritubular capillary network in a rat model of chronic kidney disease.
Figure 3: Expression of HIF-1α in experimental interstitial fibrosis.
Figure 4: The relationship between abnormal angiogenesis, inflammation and hypoxia.

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References

  1. Coresh, J., Astor, B. C., Greene, T., Eknoyan, G. & Levey, A. S. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am. J. Kidney Dis. 41, 1–12 (2003).

    PubMed  Google Scholar 

  2. Risdon, R. A., Sloper, J. C. & De Wardener, H. E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 2, 363–366 (1968).

    Article  CAS  PubMed  Google Scholar 

  3. Brezis, M. & Rosen, S. Hypoxia of the renal medulla—its implications for disease. N. Engl. J. Med. 332, 647–655 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Schurek, H. J., Jost, U., Baumgärtl, H., Bertram, H. & Heckmann, U. Evidence for a preglomerular oxygen diffusion shunt in rat renal cortex. Am. J. Physiol. 259, F910–F915 (1990).

    CAS  PubMed  Google Scholar 

  5. O'Connor, P. M., Anderson, W. P., Kett, M. M. & Evans, R. G. Renal preglomerular arterial-venous O2 shunting is a structural antioxidant defence mechanism of the renal cortex. Clin. Exp. Pharmacol. Physiol. 33, 637–641 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Kida, Y. & Duffield, J. S. Pivotal role of pericytes in kidney fibrosis. Clin. Exp. Pharmacol. Physiol. 38, 467–473 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ferrara, N. VEGF-A: a critical regulator of blood vessel growth. Eur. Cytokine Netw. 20, 158–163 (2009).

    CAS  PubMed  Google Scholar 

  9. Ferrara, N. & Davis-Smyth, T. The biology of vascular endothelial growth factor. Endocr. Rev. 18, 4–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Peiris-Pagès, M. The role of VEGF 165b in pathophysiology. Cell Adh. Migr. 6, 561–568 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Phng, L. K. et al. Nrarp coordinates endothelial Notch and Wnt signaling to control vessel density in angiogenesis. Dev. Cell 16, 70–82 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sakamoto, I. et al. Lymphatic vessels develop during tubulointerstitial fibrosis. Kidney Int. 75, 828–838 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Suzuki, Y. et al. Transforming growth factor-β induces vascular endothelial growth factor-C expression leading to lymphangiogenesis in rat unilateral ureteral obstruction. Kidney Int. 81, 865–879 (2012).

    Article  CAS  PubMed  Google Scholar 

  14. Lee, A. S. et al. Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. Kidney Int. 83, 50–62 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Bry, M. et al. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation 122, 1725–1733 (2010).

    Article  CAS  PubMed  Google Scholar 

  16. Schwartz, J. D., Rowinsky, E. K., Youssoufian, H., Pytowski, B. & Wu, Y. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1). Cancer 116, 1027–1032 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Jin, J. et al. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 151, 384–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  18. Levy, A. P., Levy, N. S., Wegner, S. & Goldberg, M. A. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J. Biol. Chem. 270, 13333–13340 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Levy, A. P., Levy, N. S. & Goldberg, M. A. Post-transcriptional regulation of vascular endothelial growth factor by hypoxia. J. Biol. Chem. 271, 2746–2753 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Takagi, H., King, G. L., Robinson, G. S., Ferrara, N. & Aiello, L. P. Adenosine mediates hypoxic induction of vascular endothelial growth factor in retinal pericytes and endothelial cells. Invest. Ophthalmol. Vis. Sci. 37, 2165–2176 (1996).

    CAS  PubMed  Google Scholar 

  21. Augustin, H. G., Koh, G. Y., Thurston, G. & Alitalo, K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat. Rev. Mol. Cell Biol. 10, 165–177 (2009).

    Article  CAS  PubMed  Google Scholar 

  22. Olsen, M. W. et al. Angiopoietin-4 inhibits angiogenesis and reduces interstitial fluid pressure. Neoplasia 8, 364–372 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu, Y., Liu, Y. J. & Yu, Q. Angiopoietin-3 inhibits pulmonary metastasis by inhibiting tumor angiogenesis. Cancer Res. 64, 6119–6126 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Lee, H. J. et al. Biological characterization of angiopoietin-3 and angiopoetin-4. FASEB J. 18, 1200–1208 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Fukuhara, S. et al. Differential function of Tie2 at cell–cell contacts and cell–substratum contacts regulated by angiopoietin-1. Nat. Cell Biol. 10, 513–526 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Saharinen, P. et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell–cell and cell–matrix contacts. Nat. Cell Biol. 10, 527–537 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Kidoya, H. et al. Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J. 27, 522–534 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Kang, D. H. et al. Role of the microvascular endothelium in progressive renal disease. J. Am. Soc. Nephrol. 13, 806–816 (2002).

    Article  PubMed  Google Scholar 

  29. Bohle, A., Mackensen-Haen, S. & Wehrmann, M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press. Res. 19, 191–195 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Kang, D. H., Hughes, J., Mazzali, M., Schreiner, G. F. & Johnson, R. J. Impaired angiogenesis in the remnant kidney model: II. Vascular endothelial growth factor administration reduces renal fibrosis and stabilizes renal function. J. Am. Soc. Nephrol. 12, 1448–1457 (2001).

    CAS  PubMed  Google Scholar 

  31. Chawla, L. S. & Kimmel, P. L. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int. 82, 516–524 (2012).

    Article  PubMed  Google Scholar 

  32. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V. & Bonventre, J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16, 535–543 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bechtel, W. et al. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat. Med. 16, 544–550 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ishii, Y. et al. Injury and progressive loss of peritubular capillaries in the development of chronic allograft nephropathy. Kidney Int. 67, 321–332 (2005).

    Article  PubMed  Google Scholar 

  35. Sutton, T. A., Fisher, C. J. & Molitoris, B. A. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int. 62, 1539–1549 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Molitoris, B. A. & Sutton, T. A. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int. 66, 496–499 (2004).

    Article  PubMed  Google Scholar 

  37. Basile, D. P., Donohoe, D., Roethe, K. & Osborn, J. L. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am. J. Physiol. Renal Physiol. 281, F887–F899 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Horbelt, M. et al. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am. J. Physiol. Renal Physiol. 293, F688–F695 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Kong, T., Eltzschig, H. K., Karhausen, J., Colgan, S. P. & Shelley, C. S. Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of β2 integrin gene expression. Proc. Natl Acad. Sci. USA 101, 10440–10445 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nangaku, M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J. Am. Soc. Nephrol. 17, 17–25 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Matsumoto, M. et al. Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J. Am. Soc. Nephrol. 15, 1574–1581 (2004).

    Article  PubMed  Google Scholar 

  42. Manotham, K. et al. Evidence of tubular hypoxia in the early phase in the remnant kidney model. J. Am. Soc. Nephrol. 15, 1277–1288 (2004).

    Article  PubMed  Google Scholar 

  43. Grgic, I. et al. Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int. 82, 172–183 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Priyadarshi, A. et al. Effects of reduction of renal mass on renal oxygen tension and erythropoietin production in the rat. Kidney Int. 61, 542–546 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Palm, F., Buerk, D. G., Carlsson, P. O., Hansell, P. & Liss, P. Reduced nitric oxide concentration in the renal cortex of streptozotocin-induced diabetic rats: effects on renal oxygenation and microcirculation. Diabetes 54, 3282–3287 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Goldfarb, M. et al. Acute-on-chronic renal failure in the rat: functional compensation and hypoxia tolerance. Am. J. Nephrol. 26, 22–33 (2006).

    Article  PubMed  Google Scholar 

  47. Tanaka, T., Miyata, T., Inagi, R., Fujita, T. & Nangaku, M. Hypoxia in renal disease with proteinuria and/or glomerular hypertension. Am. J. Pathol. 165, 1979–1992 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Safran, M. et al. Mouse model for noninvasive imaging of HIF prolyl hydroxylase activity: assessment of an oral agent that stimulates erythropoietin production. Proc. Natl Acad. Sci. USA 103, 105–110 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Gloviczki, M. L. et al. Blood oxygen level-dependent magnetic resonance imaging identifies cortical hypoxia in severe renovascular disease. Hypertension 58, 1066–1072 (2011).

    Article  CAS  PubMed  Google Scholar 

  50. Textor, S. C. et al. The use of magnetic resonance to evaluate tissue oxygenation in renal artery stenosis. J. Am. Soc. Nephrol. 19, 780–788 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. McAllister, K. A. et al. Endoglin, a TGF-β binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat. Genet. 8, 345–351 (1994).

    Article  CAS  PubMed  Google Scholar 

  52. Inoue, T. et al. Noninvasive evaluation of kidney hypoxia and fibrosis using magnetic resonance imaging. J. Am. Soc. Nephrol. 22, 1429–1434 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Wang, Z. J., Kumar, R., Banerjee, S. & Hsu, C. Y. Blood oxygen level-dependent (BOLD) MRI of diabetic nephropathy: preliminary experience. J. Magn. Reson. Imaging 33, 655–660 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Yin, W. J. et al. Noninvasive evaluation of renal oxygenation in diabetic nephropathy by BOLD-MRI. Eur. J. Radiol. 81, 1426–1431 (2012).

    Article  PubMed  Google Scholar 

  55. Brown, L. F. et al. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int. 42, 1457–1461 (1992).

    Article  CAS  PubMed  Google Scholar 

  56. Simon, M. et al. Receptors of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) in fetal and adult human kidney: localization and 125I VEGF binding sites. J. Am. Soc. Nephrol. 9, 1032–1044 (1998).

    CAS  PubMed  Google Scholar 

  57. Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Futrakul, N., Butthep, P., Laohareungpanya, N., Chaisuriya, P. & Ratanabanangkoon, K. A defective angiogenesis in chronic kidney disease. Ren. Fail. 30, 215–217 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Di Marco, G. S. et al. The soluble VEGF receptor sFlt1 contributes to endothelial dysfunction in CKD. J. Am. Soc. Nephrol. 20, 2235–2245 (2009).

    Article  CAS  PubMed  Google Scholar 

  60. Masuda, Y. et al. Vascular endothelial growth factor enhances glomerular capillary repair and accelerates resolution of experimentally induced glomerulonephritis. Am. J. Pathol. 159, 599–608 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shimizu, A. et al. Vascular endothelial growth factor165 resolves glomerular inflammation and accelerates glomerular capillary repair in rat anti-glomerular basement membrane glomerulonephritis. J. Am. Soc. Nephrol. 15, 2655–2665 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Ostendorf, T. et al. VEGF165 mediates glomerular endothelial repair. J. Clin. Invest. 104, 913–923 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hara, A. et al. Blockade of VEGF accelerates proteinuria, via decrease in nephrin expression in rat crescentic glomerulonephritis. Kidney Int. 69, 1986–1995 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Leonard, E. C., Friedrich, J. L. & Basile, D. P. VEGF121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am. J. Physiol. Renal Physiol. 295, F1648–F1657 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hohenstein, B. et al. Local VEGF activity but not VEGF expression is tightly regulated during diabetic nephropathy in man. Kidney Int. 69, 1654–1661 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Guo, M. et al. A stereological study of the renal glomerular vasculature in the db/db mouse model of diabetic nephropathy. J. Anat. 207, 813–821 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Liu, E. et al. Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. J. Am. Soc. Nephrol. 18, 2094–2104 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Hakroush, S. et al. Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. Am. J. Pathol. 175, 1883–1895 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Veron, D. et al. Overexpression of VEGF-A in podocytes of adult mice causes glomerular disease. Kidney Int. 77, 989–999 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Ku, C. H. et al. Inducible overexpression of sFlt-1 in podocytes ameliorates glomerulopathy in diabetic mice. Diabetes 57, 2824–2833 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Sivaskandarajah, G. A. et al. Vegfa protects the glomerular microvasculature in diabetes. Diabetes 61, 2958–2966 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Lindenmeyer, M. T. et al. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J. Am. Soc. Nephrol. 18, 1765–1776 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Woolf, A. S., Gnudi, L. & Long, D. A. Roles of angiopoietins in kidney development and disease. J. Am. Soc. Nephrol. 20, 239–244 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Yuan, H. T., Suri, C., Landon, D. N., Yancopoulos, G. D. & Woolf, A. S. Angiopoietin-2 is a site-specific factor in differentiation of mouse renal vasculature. J. Am. Soc. Nephrol. 11, 1055–1066 (2000).

    CAS  PubMed  Google Scholar 

  75. Kolatsi-Joannou, M., Li, X. Z., Suda, T., Yuan, H. T. & Woolf, A. S. Expression and potential role of angiopoietins and Tie-2 in early development of the mouse metanephros. Dev. Dyn. 222, 120–126 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Satchell, S. C., Anderson, K. L. & Mathieson, P. W. Angiopoietin 1 and vascular endothelial growth factor modulate human glomerular endothelial cell barrier properties. J. Am. Soc. Nephrol. 15, 566–574 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Davis, B. et al. Podocyte-specific expression of angiopoietin-2 causes proteinuria and apoptosis of glomerular endothelia. J. Am. Soc. Nephrol. 18, 2320–2329 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Futrakul, N., Butthep, P. & Futrakul, P. Altered vascular homeostasis in chronic kidney disease. Clin. Hemorheol. Microcirc. 38, 201–207 (2008).

    CAS  PubMed  Google Scholar 

  79. Yuan, H. T., Tipping, P. G., Li, X. Z., Long, D. A. & Woolf, A. S. Angiopoietin correlates with glomerular capillary loss in anti-glomerular basement membrane glomerulonephritis. Kidney Int. 61, 2078–2089 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Kim, W. et al. COMP-angiopoietin-1 ameliorates renal fibrosis in a unilateral ureteral obstruction model. J. Am. Soc. Nephrol. 17, 2474–2483 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. ten Dijke, P., Goumans, M. J. & Pardali, E. Endoglin in angiogenesis and vascular diseases. Angiogenesis 11, 79–89 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Levine, R. J. et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N. Engl. J. Med. 355, 992–1005 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Venkatesha, S. et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 12, 642–649 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Rodriguez-Pena, A. et al. Endoglin upregulation during experimental renal interstitial fibrosis in mice. Hypertension 40, 713–720 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Kang, D. H. et al. Impaired angiogenesis in the remnant kidney model: I. Potential role of vascular endothelial growth factor and thrombospondin-1. J. Am. Soc. Nephrol. 12, 1434–1447 (2001).

    CAS  PubMed  Google Scholar 

  87. Hugo, C. & Daniel, C. Thrombospondin in renal disease. Nephron Exp. Nephrol. 111, e61–e66 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Vailhe, B. & Feige, J. J. Thrombospondins as anti-angiogenic therapeutic agents. Curr. Pharm. Des. 9, 583–588 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. O'Reilly, M. S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 79, 315–328 (1994).

    Article  CAS  PubMed  Google Scholar 

  90. Sima, J., Zhang, S. X., Shao, C., Fant, J. & Ma, J. X. The effect of angiostatin on vascular leakage and VEGF expression in rat retina. FEBS Lett. 564, 19–23 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Zhang, S. X. et al. Therapeutic potential of angiostatin in diabetic nephropathy. J. Am. Soc. Nephrol. 17, 475–486 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Anand, S. & Cheresh, D. A. MicroRNA-mediated regulation of the angiogenic switch. Curr. Opin. Hematol. 18, 171–176 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Ghosh, G. et al. Hypoxia-induced microRNA-424 expression in human endothelial cells regulates HIF-α isoforms and promotes angiogenesis. J. Clin. Invest. 120, 4141–4154 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Png, K. J., Halberg, N., Yoshida, M. & Tavazoie, S. F. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 481, 190–194 (2012).

    Article  CAS  Google Scholar 

  95. Mimura, I. et al. Dynamic change of chromatin conformation in response to hypoxia enhances the expression of GLUT3 (SLC2A3) by cooperative interaction of hypoxia-inducible factor 1 and KDM3A. Mol. Cell Biol. 32, 3018–3032 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Mole, D. R. et al. Genome-wide association of hypoxia-inducible factor (HIF)-1α and HIF-2α DNA binding with expression profiling of hypoxia-inducible transcripts. J. Biol. Chem. 284, 16767–16775 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wiesener, M. S. et al. Widespread hypoxia-inducible expression of HIF-2α in distinct cell populations of different organs. FASEB J. 17, 271–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Warnecke, C. et al. The specific contribution of hypoxia-inducible factor-2α to hypoxic gene expression in vitro is limited and modulated by cell type-specific and exogenous factors. Exp. Cell Res. 314, 2016–2027 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Morita, M. et al. HLF/HIF-2α is a key factor in retinopathy of prematurity in association with erythropoietin. EMBO J. 22, 1134–1146 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Rosenberger, C. et al. Expression of hypoxia-inducible factor-1α and -2α in hypoxic and ischemic rat kidneys. J. Am. Soc. Nephrol. 13, 1721–1732 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Singh, P. et al. Aberrant tubuloglomerular feedback and HIF-1α confer resistance to ischemia after subtotal nephrectomy. J. Am. Soc. Nephrol. 23, 483–493 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Rosenberger, C. et al. Adaptation to hypoxia in the diabetic rat kidney. Kidney Int. 73, 34–42 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810–3820 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Rudnicki, M. et al. Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease. Lab. Invest. 89, 337–346 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Chade, A. R. et al. Endothelial progenitor cells restore renal function in chronic experimental renovascular disease. Circulation 119, 547–557 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Katavetin, P. et al. High glucose blunts vascular endothelial growth factor response to hypoxia via the oxidative stress-regulated hypoxia-inducible factor/hypoxia-responsible element pathway. J. Am. Soc. Nephrol. 17, 1405–1413 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Ceradini, D. J. et al. Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J. Biol. Chem. 283, 10930–10938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Chiang, C. K., Tanaka, T., Inagi, R., Fujita, T. & Nangaku, M. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab. Invest. 91, 1564–1571 (2011).

    Article  CAS  PubMed  Google Scholar 

  110. Bernhardt, W. M. et al. Organ protection by hypoxia and hypoxia-inducible factors. Methods Enzymol. 435, 221–245 (2007).

    CAS  PubMed  Google Scholar 

  111. Tanaka, T. & Nangaku, M. The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1α in progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 19, 43–50 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Tanaka, T. et al. Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model. Lab. Invest. 85, 1292–1307 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Song, Y. R. et al. Activation of hypoxia-inducible factor attenuates renal injury in rat remnant kidney. Nephrol. Dial. Transplant. 25, 77–85 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Yu, X. et al. Transient hypoxia-inducible factor activation in rat renal ablation and reduced fibrosis with L-mimosine. Nephrology (Carlton) 17, 58–67 (2012).

    Article  CAS  Google Scholar 

  115. Tanaka, T. et al. Induction of protective genes by cobalt ameliorates tubulointerstitial injury in the progressive Thy1 nephritis. Kidney Int. 68, 2714–2725 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Kobayashi, H. et al. Myeloid cell-derived hypoxia-inducible factor attenuates inflammation in unilateral ureteral obstruction-induced kidney injury. J. Immunol. 188, 5106–5115 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Schley, G. et al. Hypoxia-inducible transcription factors stabilization in the thick ascending limb protects against ischemic acute kidney injury. J. Am. Soc. Nephrol. 22, 2004–2015 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kojima, I. et al. Protective role of hypoxia-inducible factor-2α against ischemic damage and oxidative stress in the kidney. J. Am. Soc. Nephrol. 18, 1218–1226 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Chade, A. R. & Kelsen, S. Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach. Am. J. Physiol. Renal Physiol. 302, F1342–F1350 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Isner, J. M. et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 348, 370–374 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Eremina, V. et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358, 1129–1136 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Claesson-Welsh, L. & Welsh, M. VEGFA and tumour angiogenesis. J. Intern. Med. 273, 114–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  123. Flyvbjerg, A. et al. Amelioration of long-term renal changes in obese type 2 diabetic mice by a neutralizing vascular endothelial growth factor antibody. Diabetes 51, 3090–3094 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Yamamoto, Y. et al. Tumstatin peptide, an inhibitor of angiogenesis, prevents glomerular hypertrophy in the early stage of diabetic nephropathy. Diabetes 53, 1831–1840 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Ichinose, K. et al. Antiangiogenic endostatin peptide ameliorates renal alterations in the early stage of a type 1 diabetic nephropathy model. Diabetes 54, 2891–2903 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Grutzmacher, C. et al. Aberrant production of extracellular matrix proteins and dysfunction in kidney endothelial cells with short duration of diabetes. Am. J. Physiol. Renal Physiol. (2012).

  127. LeCouter, J. et al. Identification of an angiogenic mitogen selective for endocrine gland endothelium. Nature 412, 877–884 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Reinders, M. E. et al. Proinflammatory functions of vascular endothelial growth factor in alloimmunity. J. Clin. Invest. 112, 1655–1665 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. Med. 8, 831–840 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Brigati, C., Noonan, D. M., Albini, A. & Benelli, R. Tumors and inflammatory infiltrates: friends or foes? Clin. Exp. Metastasis 19, 247–258 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Long, D. A. et al. Angiopoietin-1 therapy enhances fibrosis and inflammation following folic acid-induced acute renal injury. Kidney Int. 74, 300–309 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Aplin, A. C., Gelati, M., Fogel, E., Carnevale, E. & Nicosia, R. F. Angiopoietin-1 and vascular endothelial growth factor induce expression of inflammatory cytokines before angiogenesis. Physiol. Genomics 27, 20–28 (2006).

    Article  CAS  PubMed  Google Scholar 

  133. De Palma, M. et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8, 211–226 (2005).

    Article  CAS  PubMed  Google Scholar 

  134. Lemieux, C. et al. Angiopoietins can directly activate endothelial cells and neutrophils to promote proinflammatory responses. Blood 105, 1523–1530 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Mu, W. et al. Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism. Am. J. Physiol. Renal Physiol. 296, F145–F152 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Nakao, S. et al. Larger therapeutic window for steroid versus VEGF-A inhibitor in inflammatory angiogenesis: surprisingly similar impact on leukocyte infiltration. Invest. Ophthalmol. Vis. Sci. 53, 3296–3302 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nakao, S. et al. Intravitreal anti-VEGF therapy blocks inflammatory cell infiltration and re-entry into the circulation in retinal angiogenesis. Invest. Ophthalmol. Vis. Sci. 53, 4323–4328 (2012).

    Article  CAS  PubMed  Google Scholar 

  138. Tatar, O. et al. Effect of bevacizumab on inflammation and proliferation in human choroidal neovascularization. Arch. Ophthalmol. 126, 782–790 (2008).

    Article  PubMed  Google Scholar 

  139. Henry, T. D. et al. Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am. Heart J. 142, 872–880 (2001).

    Article  CAS  PubMed  Google Scholar 

  140. Reitsma, S., Slaaf, D. W., Vink, H., van Zandvoort, M. A. & oude Egbrink, M. G. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 454, 345–359 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Shibata, S., Sasaki, T., Harpel, P. & Fillit, H. Autoantibodies to vascular heparan sulfate proteoglycan in systemic lupus erythematosus react with endothelial cells and inhibit the formation of thrombin-antithrombin III complexes. Clin. Immunol. Immunopathol. 70, 114–123 (1994).

    Article  CAS  PubMed  Google Scholar 

  142. Eto, N. et al. Protection of endothelial cells by dextran sulfate in rats with thrombotic microangiopathy. J. Am. Soc. Nephrol. 16, 2997–3005 (2005).

    Article  CAS  PubMed  Google Scholar 

  143. Elson, D. A. et al. Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α. Genes Dev. 15, 2520–2532 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Westerweel, P. E. et al. End-stage renal disease causes an imbalance between endothelial and smooth muscle progenitor cells. Am. J. Physiol. Renal Physiol. 292, F1132–F1140 (2007).

    Article  CAS  PubMed  Google Scholar 

  146. Chade, A. R. et al. Endothelial progenitor cells homing and renal repair in experimental renovascular disease. Stem Cells 28, 1039–1047 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Goligorsky, M. S., Yasuda, K. & Ratliff, B. Dysfunctional endothelial progenitor cells in chronic kidney disease. J. Am. Soc. Nephrol. 21, 911–919 (2010).

    Article  CAS  PubMed  Google Scholar 

  148. Bahlmann, F. H. et al. Low-dose therapy with the long-acting erythropoietin analogue darbepoetin α persistently activates endothelial Akt and attenuates progressive organ failure. Circulation 110, 1006–1012 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Cantaluppi, V. et al. Microvesicles derived from endothelial progenitor cells protect the kidney from ischemia–reperfusion injury by microRNA-dependent reprogramming of resident renal cells. Kidney Int. 82, 412–427 (2012).

    Article  CAS  PubMed  Google Scholar 

  150. Bruno, S. et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J. Am. Soc. Nephrol. 20, 1053–1067 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gatti, S. et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol. Dial. Transplant. 26, 1474–1483 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

    Article  CAS  PubMed  Google Scholar 

  153. Zhuang, G. et al. Tumour-secreted miR-9 promotes endothelial cell migration and angiogenesis by activating the JAK-STAT pathway. EMBO J. 31, 3513–3523 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The work of the authors is supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science 24390213 (M. Nangaku.) and 22790781 (T. Tanaka).

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Authors and Affiliations

  1. Division for Health Service Promotion, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan

    Tetsuhiro Tanaka

  2. Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, 113-8655, Tokyo, Japan

    Masaomi Nangaku

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  1. Tetsuhiro Tanaka
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Both authors researched the data for the article, wrote the manuscript and reviewed or edited the manuscript before submission.

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Correspondence to Masaomi Nangaku.

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Tanaka, T., Nangaku, M. Angiogenesis and hypoxia in the kidney. Nat Rev Nephrol 9, 211–222 (2013). https://doi.org/10.1038/nrneph.2013.35

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