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.

  • News & Views
  • Published:

CELL DEATH

A pathway of osmotic stress-induced necroptosis

Nature Reviews Nephrology volume 18, pages 609–610 (2022)Cite this article

Subjects

Necroptosis is a form of regulated necrosis in which RIPK3 is activated by binding to RIP homotypic interaction motif (RHIM)-containing proteins. Now, researchers describe a non-canonical pathway of RIPK3 activation that is triggered by osmotic stress and NHE1-mediated cytosol alkalinization. This previously undescribed mechanism of osmotic stress-induced necroptosis might have implications for treating cancer and other diseases.

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

Fig. 1: Pathways of RIPK3 activation and necroptosis.

References

  1. Linkermann, A., Stockwell, B. R., Krautwald, S. & Anders, H. J. Regulated cell death and inflammation: an auto-amplification loop causes organ failure. Nat. Rev. Immunol. 14, 759–767 (2014).

    Article  CAS  Google Scholar 

  2. Zhang, W., Fan, W., Guo, J. & Wang, X. Osmotic stress activates RIPK3/MLKL-mediated necroptosis by increasing cytosolic pH through a plasma membrane Na+/H+ exchanger. Sci. Signal. 15, eabn5881 (2022).

    Article  CAS  Google Scholar 

  3. Wakabayashi, S. et al. Overexpression of Na+/H+ exchanger 1 specifically induces cell death in human iPS cells via sustained activation of the Rho kinase ROCK. J. Biol. Chem. 294, 19577–19588 (2019).

    Article  CAS  Google Scholar 

  4. Sharifi, M. et al. Necroptosis and RhoA/ROCK pathways: molecular targets of Nesfatin-1 in cardioprotection against myocardial ischemia/reperfusion injury in a rat model. Mol. Biol. Rep. 48, 2507–2518 (2021).

    Article  CAS  Google Scholar 

  5. Martin-Sanchez, D. et al. Bone marrow-derived RIPK3 mediates kidney inflammation in acute kidney injury. J. Am. Soc. Nephrol. 33, 357–373 (2022).

    Article  CAS  Google Scholar 

  6. Zheng, T., Jäättelä, M. & Liu, B. pH gradient reversal fuels cancer progression. Int. J. Biochem. Cell Biol. 125, 105796 (2020).

    Article  CAS  Google Scholar 

  7. Lagadic-Gossmann, D., Huc, L. & Lecureur, V. Alterations of intracellular pH homeostasis in apoptosis: origins and roles. Cell Death Differ. 11, 953–961 (2004).

    Article  CAS  Google Scholar 

  8. Lins, B. B., Casare, F. A. M., Fontenele, F. F., Gonçalves, G. L. & Oliveira-Souza, M. Long-term angiotensin II infusion induces oxidative and endoplasmic reticulum stress and modulates Na+ transporters through the nephron. Front. Physiol. 12, 642752 (2021).

    Article  Google Scholar 

  9. Mentzer, R. M. Jr et al. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann. Thorac. Surg. 85, 1261–1270 (2008).

    Article  Google Scholar 

  10. Hamrah, P. & Dana, R. Toxic conjunctivitis. UpToDate https://www.uptodate.com/contents/toxic-conjunctivitis (2022).

Download references

Acknowledgements

The authors have received funding from FIS/Fondos FEDER: PI19/00588, PI19/00815, Instituto de Salud Carlos III (ISCIII) RICORS2040 (RD21/0005/0001), Financiado por la Unión Europea – NextGenerationEU and Mecanismo para la Recuperación y la Resiliencia (MRR). A.B.S. has received salary support from the Ramon y Cajal program.

Author information

Authors and Affiliations

  1. Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundacion Jimenez Diaz, Universidad Autonoma de Madrid, Madrid, Spain

    Alberto Ortiz & Ana B. Sanz

  2. Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS)2040, Madrid, Spain

    Alberto Ortiz & Ana B. Sanz

  3. Department of Medicine, Universidad Autonoma de Madrid, Madrid, Spain

    Alberto Ortiz

  4. Instituto Reina Sofia de Investigaciones Nefrologicas (IRSIN), Madrid, Spain

    Alberto Ortiz

Authors
  1. Alberto Ortiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana B. Sanz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Alberto Ortiz or Ana B. Sanz.

Ethics declarations

Competing interests

A.O. has received grants from Sanofi and consultancy or speaker fees or travel support from Advicciene, Astellas, Astrazeneca, Amicus, Amgen, Fresenius Medical Care, GSK, Bayer, Sanofi-Genzyme, Menarini, Mundipharma, Kyowa Kirin, Alexion, Freeline, Idorsia, Chiesi, Otsuka, Novo-Nordisk, Sysmex and Vifor Fresenius Medical Care Renal Pharma, and is Director of the Catedra Mundipharma-UAM of DKD and the Catedra Astrazeneca-UAM of CKD and electrolytes. A.B.S. declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ortiz, A., Sanz, A.B. A pathway of osmotic stress-induced necroptosis. Nat Rev Nephrol 18, 609–610 (2022). https://doi.org/10.1038/s41581-022-00607-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-022-00607-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing