Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Klotho as a potential biomarker and therapy for acute kidney injury

Nature Reviews Nephrology volume 8, pages 423–429 (2012)Cite this article

Subjects

Abstract

Klotho is a single-pass transmembrane protein that is highly expressed in the kidney and is known to act as a coreceptor for fibroblast growth factor 23. The extracellular domain can be produced independently or shed from membrane-bound Klotho and functions as an endocrine substance with multiple functions including antioxidation, modulation of ion transport, suppression of fibrosis, and preservation of stem cells. Emerging evidence has revealed that Klotho deficiency is an early event in acute kidney injury (AKI), and a pathogenic factor that exacerbates acute kidney damage and contributes to long-term consequences. Restoration by exogenous supplementation or stimulation of endogenous Klotho might prevent and ameliorate injury, promote recovery, and suppress fibrosis to mitigate development of chronic kidney disease. Although data are still emerging, in this Perspectives article we discuss why this renal-derived protein is a highly promising candidate as both an early biomarker and therapeutic agent for AKI.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proposed mechanisms by which Klotho exerts its beneficial effects on renal epithelia in acute ischemia–reperfusion injury.

Similar content being viewed by others

References

  1. Fonseca Ruiz, N. J., Castro, D. P., Guerra, A. M., Saldarriaga, F. M. & Hernandez, J. D. Renal injury study in critical ill patients in accordance with the new definition given by the Acute Kidney Injury Network. J. Crit. Care 26, 206–212 (2011).

    Article  Google Scholar 

  2. Akcan-Arikan, A. et al. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 71, 1028–1035 (2007).

    Article  CAS  Google Scholar 

  3. Waikar, S. S., Curhan, G. C., Ayanian, J. Z. & Chertow, G. M. Race and mortality after acute renal failure. J. Am. Soc. Nephrol. 18, 2740–2748 (2007).

    Article  Google Scholar 

  4. Wald, R. et al. Chronic dialysis and death among survivors of acute kidney injury requiring dialysis. JAMA 302, 1179–1185 (2009).

    Article  CAS  Google Scholar 

  5. Hsu, C. Y. et al. Nonrecovery of kidney function and death after acute on chronic renal failure. Clin. J. Am. Soc. Nephrol. 4, 891–898 (2009).

    Article  Google Scholar 

  6. Kuro-o, M. et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390, 45–51 (1997).

    Article  CAS  Google Scholar 

  7. Ito, S. et al. Molecular cloning and expression analyses of mouse βklotho, which encodes a novel Klotho family protein. Mech. Dev. 98, 115–119 (2000).

    Article  CAS  Google Scholar 

  8. Tomiyama, K. et al. Relevant use of Klotho in FGF19 subfamily signaling system in vivo. Proc. Natl Acad. Sci. USA 107, 1666–1671 (2010).

    Article  CAS  Google Scholar 

  9. Kurosu, H. et al. Regulation of fibroblast growth factor-23 signaling by klotho. J. Biol. Chem. 281, 6120–6123 (2006).

    Article  CAS  Google Scholar 

  10. Kurosu, H. et al. Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J. Biol. Chem. 282, 26687–26695 (2007).

    Article  CAS  Google Scholar 

  11. Goetz, R. et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol. Cell. Biol. 27, 3417–3428 (2007).

    Article  CAS  Google Scholar 

  12. Matsumura, Y. et al. Identification of the human klotho gene and its two transcripts encoding membrane and secreted klotho protein. Biochem. Biophys. Res. Commun. 242, 626–630 (1998).

    Article  CAS  Google Scholar 

  13. Shiraki-Iida, T. et al. Structure of the mouse klotho gene and its two transcripts encoding membrane and secreted protein. FEBS Lett. 424, 6–10 (1998).

    Article  CAS  Google Scholar 

  14. Imura, A. et al. Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett. 565, 143–147 (2004).

    Article  CAS  Google Scholar 

  15. Hu, M. C. et al. Klotho: a novel phosphaturic substance acting as an autocrine enzyme in the renal proximal tubule. FASEB J. 24, 3438–3450 (2010).

    Article  CAS  Google Scholar 

  16. Chen, C. D., Podvin, S., Gillespie, E., Leeman, S. E. & Abraham, C. R. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc. Natl Acad. Sci. USA 104, 19796–19801 (2007).

    Article  CAS  Google Scholar 

  17. Bloch, L. et al. Klotho is a substrate for α-, β- and γ-secretase. FEBS Lett. 583, 3221–3224 (2009).

    Article  CAS  Google Scholar 

  18. Liu, H. et al. Augmented Wnt signaling in a mammalian model of accelerated aging. Science 317, 803–806 (2007).

    Article  CAS  Google Scholar 

  19. Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005).

    Article  CAS  Google Scholar 

  20. Liu, F., Wu, S., Ren, H. & Gu, J. Klotho suppresses RIG-I-mediated senescence-associated inflammation. Nat. Cell Biol. 13, 254–262 (2011).

    Article  CAS  Google Scholar 

  21. German, D. C., Khobahy, I., Pastor, J., Kuro, O. M. & Liu, X. Nuclear localization of Klotho in brain: an anti-aging protein. Neurobiol. Aging http://dx.doi.org/10.1016/j.neurobiolaging.2011.12.018.

  22. Hu, M. C. et al. Klotho deficiency is an early biomarker of renal ischemia-reperfusion injury and its replacement is protective. Kidney Int. 78, 1240–1251 (2010).

    Article  CAS  Google Scholar 

  23. Sugiura, H. et al. Klotho reduces apoptosis in experimental ischaemic acute kidney injury via HSP-70. Nephrol. Dial. Transplant. 25, 60–68 (2010).

    Article  CAS  Google Scholar 

  24. Mitobe, M. et al. Oxidative stress decreases klotho expression in a mouse kidney cell line. Nephron Exp. Nephrol. 101, e67–e74 (2005).

    Article  CAS  Google Scholar 

  25. Maekawa, Y. et al. Klotho protein diminishes endothelial apoptosis and senescence via a mitogen-activated kinase pathway. Geriatr. Gerontol. Int. 11, 510–516 (2011).

    Article  Google Scholar 

  26. Rakugi, H. et al. Anti-oxidative effect of Klotho on endothelial cells through cAMP activation. Endocrine 31, 82–87 (2007).

    Article  CAS  Google Scholar 

  27. Hu, M. C., Kuro-o, M. & Moe, O. W. Secreted klotho and chronic kidney disease. Adv. Exp. Med. Biol. 728, 126–157 (2012).

    Article  CAS  Google Scholar 

  28. Doi, S. et al. Klotho inhibits transforming growth factor-β1 (TGF-β1) signaling and suppresses renal fibrosis and cancer metastasis in mice. J. Biol. Chem. 286, 8655–8665 (2011).

    Article  CAS  Google Scholar 

  29. Ohyama, Y. et al. Molecular cloning of rat klotho cDNA: markedly decreased expression of klotho by acute inflammatory stress. Biochem. Biophys. Res. Commun. 251, 920–925 (1998).

    Article  CAS  Google Scholar 

  30. Tang, C. et al. Downregulation of Klotho expression by dehydration. Am. J. Physiol. Renal Physiol. 301, F745–F750 (2011).

    Article  CAS  Google Scholar 

  31. Panesso, M. C. et al. Klotho ameliorates cisplatin nephrotoxicity. J. Am. Soc. Nephrol. 22 (Suppl.), TH-PO027 (2011).

    Google Scholar 

  32. Moreno, J. A. et al. The inflammatory cytokines TWEAK and TNFα reduce renal Klotho expression through NFκB. J. Am. Soc. Nephrol. 22, 1315–1325 (2011).

    Article  CAS  Google Scholar 

  33. Sugiura, H. et al. Klotho reduces apoptosis in experimental ischaemic acute renal failure. Nephrol. Dial. Transplant. 20, 2636–2645 (2005).

    Article  CAS  Google Scholar 

  34. Ohata, Y. et al. Circulating levels of soluble α-Klotho are markedly elevated in human umbilical cord blood. J. Clin. Endocrinol. Metab. 96, E943–E947 (2011).

    Article  CAS  Google Scholar 

  35. Semba, R. D. et al. Plasma klotho and mortality risk in older community-dwelling adults. J. Gerontol. A Biol. Sci. Med. Sci. 66, 794–800 (2011).

    Article  Google Scholar 

  36. Semba, R. D. et al. Relationship of low plasma klotho with poor grip strength in older community-dwelling adults: the InCHIANTI study. Eur. J. Appl. Physiol. 112, 1215–1220 (2012).

    Article  Google Scholar 

  37. Devaraj, S., Syed, B., Chien, A. & Jialal, I. Validation of an immunoassay for soluble klotho protein: decreased levels in diabetes and increased levels in chronic kidney disease. Am. J. Clin. Pathol. 137, 479–485 (2012).

    Article  CAS  Google Scholar 

  38. Semba, R. D. et al. Plasma Klotho and cardiovascular disease in adults. J. Am. Geriatr. Soc. 59, 1596–1601 (2011).

    Article  Google Scholar 

  39. Pavik, I. et al. Soluble klotho and autosomal dominant polycystic kidney disease. Clin. J. Am. Soc. Nephrol. 7, 248–257 (2012).

    Article  CAS  Google Scholar 

  40. Yamazaki, Y. et al. Establishment of sandwich ELISA for soluble α-Klotho measurement: age-dependent change of soluble α-Klotho levels in healthy subjects. Biochem. Biophys. Res. Commun. 398, 513–518 (2010).

    Article  CAS  Google Scholar 

  41. Huang, C. L. & Moe, O. W. Klotho: a novel regulator of calcium and phosphorus homeostasis. Pflugers Arch. 462, 185–193 (2011).

    Article  CAS  Google Scholar 

  42. Schrier, R. W. Diagnostic value of urinary sodium, chloride, urea, and flow. J. Am. Soc. Nephrol. 22, 1610–1613 (2011).

    Article  CAS  Google Scholar 

  43. Parikh, C. R. et al. Postoperative biomarkers predict acute kidney injury and poor outcomes after adult cardiac surgery. J. Am. Soc. Nephrol. 22, 1748–1757 (2011).

    Article  CAS  Google Scholar 

  44. Parikh, C. R. et al. Postoperative biomarkers predict acute kidney injury and poor outcomes after pediatric cardiac surgery. J. Am. Soc. Nephrol. 22, 1737–1747 (2011).

    Article  CAS  Google Scholar 

  45. Perco, P. & Oberbauer, R. Kidney injury molecule-1 as a biomarker of acute kidney injury in renal transplant recipients. Nat. Clin. Pract. Nephrol. 4, 362–363 (2008).

    Article  CAS  Google Scholar 

  46. Vaidya, V. S. et al. A rapid urine test for early detection of kidney injury. Kidney Int. 76, 108–114 (2009).

    Article  CAS  Google Scholar 

  47. Devarajan, P. Biomarkers for the early detection of acute kidney injury. Curr. Opin. Pediatr. 23, 194–200 (2011).

    Article  CAS  Google Scholar 

  48. Liang, X. L. et al. Combination of urinary kidney injury molecule-1 and interleukin-18 as early biomarker for the diagnosis and progressive assessment of acute kidney injury following cardiopulmonary bypass surgery: a prospective nested case-control study. Biomarkers 15, 332–339 (2010).

    Article  CAS  Google Scholar 

  49. King, G. D., Rosene, D. L. & Abraham, C. R. Promoter methylation and age-related downregulation of Klotho in rhesus monkey. Age (Dordr.) http://dx.doi.10.1007/s11357-011-9315-4.

  50. Thurston, R. D. et al. Tumor necrosis factor and interferon-γ down-regulate Klotho in mice with colitis. Gastroenterology 138, 1384–1394 (2010).

    Article  CAS  Google Scholar 

  51. Zarjou, A., Yang, S., Abraham, E., Agarwal, A. & Liu, G. Identification of a microRNA signature in renal fibrosis: role of miR-21. Am. J. Physiol. Renal Physiol. 301, F793–F801 (2011).

    Article  CAS  Google Scholar 

  52. Bhatt, K., Mi, Q. S. & Dong, Z. microRNAs in kidneys: biogenesis, regulation, and pathophysiological roles. Am. J. Physiol. Renal Physiol. 300, F602–F610 (2011).

    Article  CAS  Google Scholar 

  53. Madias, N. E. & Harrington, J. T. Platinum nephrotoxicity. Am. J. Med. 65, 307–314 (1978).

    Article  CAS  Google Scholar 

  54. Haruna, Y. et al. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc. Natl Acad. Sci. USA 104, 2331–2336 (2007).

    Article  CAS  Google Scholar 

  55. de Oliveira, R. M. Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway. FEBS Lett. 580, 5753–5758 (2006).

    Article  Google Scholar 

  56. Ortiz, A., Gonzalez Cuadrado, S., Lorz, C. & Egido, J. Apoptosis in renal diseases. Front. Biosci. 1, d30–d47 (1996).

    Article  CAS  Google Scholar 

  57. Yamamoto, M. et al. Regulation of oxidative stress by the anti-aging hormone Klotho. J. Biol. Chem. 280, 38029–38034 (2005).

    Article  CAS  Google Scholar 

  58. Chawla, L. S., Amdur, R. L., Amodeo, S., Kimmel, P. L. & Palant, C. E. The severity of acute kidney injury predicts progression to chronic kidney disease. Kidney Int. 79, 1361–1369 (2011).

    Article  Google Scholar 

  59. Forbes, J. M., Hewitson, T. D., Becker, G. J. & Jones, C. L. Ischemic acute renal failure: long-term histology of cell and matrix changes in the rat. Kidney Int. 57, 2375–2385 (2000).

    Article  CAS  Google Scholar 

  60. 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  Google Scholar 

  61. 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  Google Scholar 

  62. Sugiura, H. et al. TGF-β was upregulated in renal fibrosis model of Klotho defect mouse and affected renal Klotho expression level [abstract]. J. Am. Soc. Nephrol. 21, 376A (2010).

    Google Scholar 

  63. Samarakoon, R., Overstreet, J. M., Higgins, S. P. & Higgins, P. J. TGF-β1 → SMAD/p53/USF2 → PAI-1 transcriptional axis in ureteral obstruction-induced renal fibrosis. Cell Tissue Res. 347, 117–128 (2012).

    Article  CAS  Google Scholar 

  64. Li, X. et al. Synergistic effect of hypoxia and TNF-α on production of PAI-1 in human proximal renal tubular cells. Kidney Int. 68, 569–583 (2005).

    Article  CAS  Google Scholar 

  65. Takeshita, K. et al. Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, “Klotho” mouse. Semin. Thromb. Hemost. 28, 545–554 (2002).

    Article  CAS  Google Scholar 

  66. Sugiura, H. et al. Reduced Klotho expression level in kidney aggravates renal interstitial fibrosis. Am. J. Physiol. Renal Physiol. http://dx.doi:10.1152/ajprenal.00294-2011.

  67. Basile, D. P. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 72, 151–156 (2007).

    Article  CAS  Google Scholar 

  68. Brodsky, S. V. et al. Endothelial dysfunction in ischemic acute renal failure: rescue by transplanted endothelial cells. Am. J. Physiol. Renal Physiol. 282, F1140–F1149 (2002).

    Article  CAS  Google Scholar 

  69. Gueler, F. et al. Postischemic acute renal failure is reduced by short-term statin treatment in a rat model. J. Am. Soc. Nephrol. 13, 2288–2298 (2002).

    Article  CAS  Google Scholar 

  70. Chade, A. R. et al. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. FASEB J. 20, 1706–1708 (2006).

    Article  CAS  Google Scholar 

  71. Narumiya, H. et al. HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA inactivation in IMCD3 cells. Cardiovasc. Res. 64, 331–336 (2004).

    Article  CAS  Google Scholar 

  72. King, G. D. et al. Identification of novel small molecules that elevate Klotho expression. Biochem. J. 441, 453–461 (2012).

    Article  CAS  Google Scholar 

  73. Yamagishi, T. et al. Troglitazone improves endothelial function and augments renal klotho mRNA expression in Otsuka Long-Evans Tokushima Fatty (OLETF) rats with multiple atherogenic risk factors. Hypertens. Res. 24, 705–709 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors were supported by the NIH (R01-DK091392 and R01-DK092461), the George M. O'Brien Kidney Research Center/University of Texas Southwestern Medical Center (P30-DK-07938), American Heart Association (0865235F), the Simmons Family Foundation and a Seed Grant from the Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center. The authors would like to thank M. Kuro-o for long-term valuable collaboration, and M. Shi for expert assistance with some key experiments performed in the authors' laboratories cited in this article.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-8885, TX, USA

    Ming-Chang Hu & Orson W. Moe

Authors
  1. Ming-Chang Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Orson W. Moe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ming-Chang Hu or Orson W. Moe.

Ethics declarations

Competing interests

M.–C. Hu has received grant support from the American Heart Association and NIH. O. W. Moe has received grant support from the NIH and Simmons Family Foundation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hu, MC., Moe, O. Klotho as a potential biomarker and therapy for acute kidney injury. Nat Rev Nephrol 8, 423–429 (2012). https://doi.org/10.1038/nrneph.2012.92

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.92

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research