Novel Therapeutic Approach Targeting The Hif-Hre System In The Kidney

  • Masaomi Nangaku
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 645)


Recent studies emphasize the role of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease. Therefore, therapeutic approaches which target the chronic hypoxia should prove effective against a broad range of renal diseases.

Many of hypoxia-triggered protective mechanisms are hypoxia inducible factor (HIF)-dependent. Although HIF-1α and HIF-2α share both structural and functional similarity, they have different localization and can contribute in a non-redundant manner. While gene transfer of constitutively active HIF has been shown effective, pharmacological approaches to activate HIF are more desirable. Oxygen-dependent activation of prolyl hydroxylases (PHD) regulates the amount of HIF by degradation of this transcription factor. Therefore, PHD inhibitors have been the focus of recent studies on novel strategies to stabilize HIF. Cobalt is one of the inhibitors of PHD, and stimulation of HIF with cobalt is effective in a variety of kidney disease models. Furthermore, crystal structures of the catalytic domain of human prolyl hydroxylase 2 have been clarified recently. The structure aids in the design of PHD selective inhibitors for the treatment of hypoxic tissue injury.

Current advance has elucidated the detailed mechanism of hypoxia-induced transcription, giving hope for the development of novel therapeutic approaches against hypoxia.


Chronic Hypoxia Critical Limb Ischemia Prolyl Hydroxylase Final Common Pathway Tubulointerstitial Injury 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    M. Nangaku, Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure, J. Am. Soc. Nephrol. 17(1), 17-25 (2006)PubMedCrossRefGoogle Scholar
  2. 2.
    T. Tanaka, T. Miyata, R. Inagi, T. Fujita, and M. Nangaku, Hypoxia in renal disease with proteinuria and/or glomerular hypertension. Am. J. Pathol. 165(6), 1979-92 (2004)PubMedGoogle Scholar
  3. 3.
    F. Palm, J. Cederberg, P. Hansell, P. Liss, and P.O. Carlsson, Reactive oxygen species cause diabetes-induced decrease in renal oxygen tension, Diabetologia. 46(8), 1153-60 (2003)PubMedCrossRefGoogle Scholar
  4. 4.
    C. Rosenberger, S. Mandriota, J.S. Jurgensen, M.S. Wiesener, J.H. Horstrup, U. Frei, P.J. Ratcliffe, P.H. Maxwell, S. Bachmann, and K.U. Eckardt, Expression of hypoxia-inducible factor-1 and -2 in hypoxic and ischemic rat kidneys, J. Am. Soc. Nephrol. 13(7), 1721-1732 (2002)Google Scholar
  5. 5.
    M.S. Wiesener, J.S. Jurgensen, C. Rosenberger, C.K. Scholze, J.H. Horstrup, C. Warnecke, S. Mandriota, I. Bechmann, U.A. Frei, C.W. Pugh, P.J. Ratcliffe, S. Bachmann, P.H. Maxwell, and K.U. Eckardt, Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs, FASEB J. 17, 271-273 (2003)PubMedGoogle Scholar
  6. 6.
    C. Rosenberger, W. Griethe, G. Gruber, M. Wiesener, U. Frei, S. Bachmann, and K.U. Eckardt, Cellular responses to hypoxia after renal segmental infarction, Kidney Int. 64(3), 874-886 (2003)PubMedCrossRefGoogle Scholar
  7. 7.
    C. Rosenberger, S.N. Heyman, S. Rosen, A. Shina, M. Goldfarb, W. Griethe, U. Frei, P. Reinke, S. Bachmann, and K.U. Eckardt, Up-regulation of HIF in experimental acute renal failure: evidence for a protective transcriptional response to hypoxia. Kidney Int. 67(2), 531-542 (2005)PubMedCrossRefGoogle Scholar
  8. 8.
    Z. Cai, D.J. Manalo, G. Wei, E.R. Rodriguez, K. Fox-Talbot, H. Lu, J.L. Zweier, and G.L. Semenza GL, Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury, Circulation. 108(1), 79-85 (2003)PubMedCrossRefGoogle Scholar
  9. 9.
    I. Kojima, T. Tanaka, R. Inagi, H. Kato, T. Yamashita, A. Sakiyama, O. Ohneda, N. Takeda, M. Sata, T. Miyata, T. Fujita T, and M. Nangaku, Protective role of hypoxia-inducible factor-2alpha against ischemic damage and oxidative stress in the kidney, J. Am. Soc. Nephrol. 18(4), 1218-26 (2007)PubMedCrossRefGoogle Scholar
  10. 10.
    N. Li, F. Yi, C.M. Sundy, L. Chen, M.L. Hilliker, D.K. Donley, D.B. Muldoon, and P.L. Li, Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys, Am. J. Physiol. Renal Physiol. 292(1), F207-16 (2007)PubMedCrossRefGoogle Scholar
  11. 11.
    C. Willam, P.H. Maxwell, L. Nichols, C. Lygate, Y.M. Tian, W. Bernhardt, M. Wiesener, P.J. Ratcliffe, K.U. Eckardt, and C.W. Pugh, HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation, J. Mol. Cell. Cardiol. 41, 68-77 (2006)PubMedCrossRefGoogle Scholar
  12. 12.
    R.J. Appelhoff, Y.M. Tian, R.R. Raval, H. Turley, A.L. Harris, C.W. Pugh, P.J. Ratcliffe, and J.M. Gleadle, Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor, J. Biol. Chem. 279(37), 38458-38465 (2004)PubMedCrossRefGoogle Scholar
  13. 13.
    K. Takeda, A. Cowan, and G.H. Fong, Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system, Circulation. [Epub ahead of print] (2007)Google Scholar
  14. 14.
    K. Manotham, T. Tanaka, T. Ohse, I. Kojima, T. Miyata, R. Inagi, H. Tanaka, R. Sassa, T. Fujita, and M. Nangaku, A biological role of HIF-1 in the renal medulla, Kidney Int. 67(4), 1428-1439 (2005)PubMedCrossRefGoogle Scholar
  15. 15.
    S. Rajagopalan, J. Olin, S. Deitcher, A. Pieczek, J. Laird, P.M. Grossman, C.K. Goldman, K. McEllin, R. Kelly, and N. Chronos, Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience, Circulation. 115(10), 1234-43 (2007)PubMedGoogle Scholar
  16. 16.
    H.F. Gardner, The use of cobaltous chloride in the anemia associated with chronic renal disease. J. Lab. Clin. Med. 41(1), 56-64 (1953)PubMedGoogle Scholar
  17. 17.
    M. Matsumoto, Y. Makino, T. Tanaka, H. Tanaka, N. Ishizaka, E. Noiri, T. Fujita, and M. Nangaku, Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats, J. Am. Soc. Nephrol. 14(7), 1825-1832 (2003)PubMedCrossRefGoogle Scholar
  18. 18.
    Y. Kudo, Y. Kakinuma, Y. Mori, N. Morimoto, T. Karashima, M. Furihata, T. Sato, T. Shuin, and T. Sugiura, Hypoxia-inducible factor-1alpha is involved in the attenuation of experimentally induced rat glomerulonephritis, Nephron Exp. Nephrol. 100(2), e95-103 (2005)PubMedCrossRefGoogle Scholar
  19. 19.
    T. Tanaka, I. Kojima, T. Ohse, J.R. Ingelfinger, S. Adler, T. Fujita, and M. Nangaku, Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model, Lab. Invest. 85(10), 1292-1307 (2005)Google Scholar
  20. 20.
    T. Tanaka, I. Kojima, T. Ohse, R. Inagi, T. Miyata, J.R. Ingelfinger, T. Fujita, and M. Nangaku, Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity. Am. J. Physiol. Renal Physiol. 289(5), F1123-1133 (2005)PubMedCrossRefGoogle Scholar
  21. 21.
    T. Tanaka, M. Matsumoto, R. Inagi, T. Miyata, I. Kojima, T. Ohse, T. Fujita, and M. Nangaku, Induction of protective genes by cobalt ameliorates tubulointerstitial injury in the progressive Thy1 nephritis, Kidney Int. 68(6), 2714-2725 (2005)PubMedCrossRefGoogle Scholar
  22. 22.
    C. Warnecke, W. Griethe, A. Weidemann, J.S. Jurgensen, C. Willam, S. Bachmann, Y. Ivashchenko, I. Wagner, U. Frei, M. Wiesener, and K.U. Eckardt, Activation of the hypoxia-inducible factor-pathway and stimulation of angiogenesis by application of prolyl hydroxylase inhibitors, FASEB J. 17, 1186-1188 (2003)PubMedGoogle Scholar
  23. 23.
    H. Kasiganesan, V. Sridharan, and G. Wright, Prolyl hydroxylase inhibitor treatment confers whole-animal hypoxia tolerance, Acta Physiol. (Oxf). 190(2), 163-9 (2007)CrossRefGoogle Scholar
  24. 24.
    W.M. Bernhardt, V. Campean, S. Kany, J.S. Jürgensen, A. Weidemann, C. Warnecke, M. Arend, S. Klaus, V. Günzler, K. Amann, C. Willam, M.S. Wiesener, and K.U. Eckardt, Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure, J. Am. Soc. Nephrol. 17(7), 1970-1978 (2006)PubMedCrossRefGoogle Scholar
  25. 25.
    M.A. McDonough, V. Li, E. Flashman, R. Chowdhury, C. Mohr, B.M. Liénard, J. Zondlo, N.J. Oldham, I.J. Clifton, J. Lewis, L.A. McNeill, R.J. Kurzeja, K.S. Hewitson, E. Yang, S. Jordan, R.S. Syed, and C.J. Schofield, Cellular oxygen sensing: Crystal structure of hypoxia-inducible factor prolyl hydroxylase (PHD2), Proc. Natl. Acad. Sci. 103(26), 9814-9819 (2006)PubMedCrossRefGoogle Scholar
  26. 26.
    E.J. Soilleux, H. Turley, Y.M. Tian, C.W. Pugh, K.C. Gatter, and A.L. Harris AL, Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues, Histopathology. 47(6), 602–610 (2005)PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Masaomi Nangaku
    • 1
  1. 1.Division of Nephrology and EndocrinologyUniversity of Tokyo School of MedicineBunkyo-kuJapan

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