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.

  • Article
  • Published:

Renalase improves pressure overload-induced heart failure in rats by regulating extracellular signal-regulated protein kinase 1/2 signaling

Hypertension Research volume 44, pages 481–488 (2021)Cite this article

Abstract

Renalase, a novel flavoprotein that is mainly expressed in the kidney and heart, plays a crucial role in hypertension. Recent studies have shown that renalase is expressed at low levels in the serum of patients with heart failure, while the role of renalase and its mechanism in cardiac failure is unclear. Adult Sprague-Dawley (SD) rats were used to investigate the role and function of renalase in the pathological process of transverse aortic constriction (TAC)-induced heart failure. Renalase-human protein chip analysis showed that renalase was directly associated with P38 and extracellular signal-regulated protein kinase 1/2 (ERK1/2) signaling. We further used lentivirus-mediated RNA interference to study the role of renalase in the progression of pathological ventricular hypertrophy and found that renalase inhibition attenuated the noradrenaline-induced hypertrophic response in vitro or the pressure overload-induced hypertrophic response in vivo. Recombinant renalase protein significantly alleviated pressure overload-induced cardiac failure and was associated with P38 and ERK1/2 signaling. These findings demonstrate that renalase is a potential biomarker of hypertrophy and that exogenous recombinant renalase is a potential and novel drug for heart failure.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Lewington S, Lacey B, Clarke R, Guo Y, Kong XL, Yang L, et al. The burden of hypertension and associated risk for cardiovascular mortality in China. JAMA Intern Med. 2016;176:524–32.

    Article  Google Scholar 

  2. Pitt B. Mark Nicholls speaks to Professor Bertram Pitt and his role as a pioneer in cardiology over the management of heart failure. Eur Heart J. 2020;41:1615–7.

  3. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020;17:559–73.

    Article  CAS  Google Scholar 

  4. Cuspidi C, Sala C, Negri F, Mancia G, Morganti A. Prevalence of left-ventricular hypertrophy in hypertension: an updated review of echocardiographic studies. J Hum Hypertens. 2012;26:343–9.

    Article  CAS  Google Scholar 

  5. Shimizu I, Minamino T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol. 2016;97:245–62.

    Article  CAS  Google Scholar 

  6. Bombelli M, Facchetti R, Carugo S, Madotto F, Arenare F, Quarti-Trevano F, et al. Left ventricular hypertrophy increases cardiovascular risk independently of in-office and out-of-office blood pressure values. J Hypertens. 2009;27:2458–64.

    Article  CAS  Google Scholar 

  7. Xu J, Li G, Wang P, Velazquez H, Yao X, Li Y, et al. Renalase is a novel, soluble monoamine oxidase that regulates cardiac function and blood pressure. J Clin Invest. 2005;115:1275–80.

    Article  CAS  Google Scholar 

  8. Luft FC. Renalase, a catecholamine-metabolizing hormone from the kidney. Cell Metab. 2005;1:358–60.

    Article  CAS  Google Scholar 

  9. Li G, Xu J, Wang P, Velazquez H, Li Y, Wu Y, et al. Catecholamines regulate the activity, secretion, and synthesis of renalase. Circulation. 2008;117:1277–82.

    Article  CAS  Google Scholar 

  10. Desir GV, Wang L, Peixoto AJ. Human renalase: a review of its biology, function, and implications for hypertension. J Am Soc Hypertens. 2012;6:417–26.

    Article  CAS  Google Scholar 

  11. Desir GV. Regulation of blood pressure and cardiovascular function by renalase. Kidney Int. 2009;76:366–70.

    Article  CAS  Google Scholar 

  12. Wu Y, Xu J, Velazquez H, Wang P, Li G, Liu D, et al. Renalase deficiency aggravates ischemic myocardial damage. Kidney Int. 2011;79:853–60.

    Article  CAS  Google Scholar 

  13. Lee IT, Sheu WH. Serum renalase levels are predicted by brain-derived neurotrophic factor and associated with cardiovascular events and mortality after percutaneous coronary intervention. J Clin Med. 2018;7:437.

    Article  CAS  Google Scholar 

  14. Safdar B, Guo X, Johnson C, D’Onofrio G, Dziura J, Sinusas AJ, et al. Elevated renalase levels in patients with acute coronary microvascular dysfunction - a possible biomarker for ischemia. Int J Cardiol. 2019;279:155–61.

    Article  Google Scholar 

  15. Li X, Xie Z, Lin M, Huang R, Liang Z, Huang W, et al. Renalase protects the cardiomyocytes of Sprague-Dawley rats against ischemia and reperfusion injury by reducing myocardial cell necrosis and apoptosis. Kidney Blood Press Res. 2015;40:215–22.

    Article  CAS  Google Scholar 

  16. Guo X, Hollander L, MacPherson D, Wang L, Velazquez H, Chang J, et al. Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer. Sci Rep. 2016;6:22996.

    Article  CAS  Google Scholar 

  17. Hollander L, Guo X, Velazquez H, Chang J, Safirstein R, Kluger H, et al. Renalase expression by melanoma and tumor-associated macrophages promotes tumor growth through a STAT3-mediated mechanism. Cancer Res. 2016;76:3884–94.

    Article  CAS  Google Scholar 

  18. Stojanovic D, Mitic V, Petrovic D, Stojanovic M, Ignjatovic A, Stefanovic N, et al. Association of plasma renalase and left ventricle mass index in heart failure patients stratified to the category of the ejection fraction: a pilot study. Dis Markers. 2019;2019:7265160.

    Article  Google Scholar 

  19. Stojanovic D, Mitic V, Stojanovic M, Petrovic D, Ignjatovic A, Stefanovic N, et al. The partnership between renalase and ejection fraction as a risk factor for increased cardiac remodeling biomarkers in chronic heart failure patients. Curr Med Res Opin. 2020;36:909–19.

    Article  CAS  Google Scholar 

  20. Li X, Lin M, Xie Z, Huang R, Chen AF, Jiang W. Establishing a low-expression renalase gene model in cardiac tissue of Sprague-Dawley rats. Herz. 2016;41:326–30.

    Article  CAS  Google Scholar 

  21. Li X, Jiang W, Li L, Huang R, Yang Q, Yang Y, et al. Renalase gene polymorphism in patients with hypertension and concomitant coronary heart disease. Kidney Blood Press Res. 2014;39:9–16.

    Article  Google Scholar 

  22. Wybraniec MT, Wieczorek J, Wozniak-Skowerska I, Hoffmann A, Nowak S, Cichon M, et al. Renalase is associated with adverse left atrial remodelling and disease burden in patients with atrial fibrillation undergoing pulmonary vein isolation. Kardiol Pol. 2018;76:1232–41.

    Article  Google Scholar 

  23. Schlaich MP, Lambert GW, Eikelis N. Renalase - a potential biomarker for risk of atrial fibrillation? Kardiol pol. 2018;76:1201–2.

    Article  Google Scholar 

  24. Jiang W, Tan L, Guo Y, Li X, Tang X, Yang K. Effect of renal denervation procedure on left ventricular hypertrophy of hypertensive rats and its mechanisms. Acta Cir Bras. 2012;27:815–20.

    Article  Google Scholar 

  25. Wang L, Velazquez H, Chang J, Safirstein R, Desir GV. Identification of a receptor for extracellular renalase. Plos ONE. 2015;10:e122932.

    Google Scholar 

  26. Wang Y, Safirstein R, Velazquez H, Guo XJ, Hollander L, Chang J, et al. Extracellular renalase protects cells and organs by outside-in signalling. J Cell Mol Med. 2017;21:1260–5.

    Article  CAS  Google Scholar 

  27. Hoag MR, Roman J, Beaupre BA, Silvaggi NR, Moran GR. Bacterial renalase: structure and kinetics of an enzyme with 2- and 6-Dihydro-beta-NAD(P) oxidase activity from pseudomonas phaseolicola. Biochemistry-US. 2015;54:3791–802.

    Article  CAS  Google Scholar 

  28. Zhao L, Cheng G, Jin R, Afzal MR, Samanta A, Xuan YT, et al. Deletion of interleukin-6 attenuates pressure overload-induced left ventricular hypertrophy and dysfunction. Circ Res. 2016;118:1918–29.

    Article  CAS  Google Scholar 

  29. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57.

    Article  CAS  Google Scholar 

  30. Miao R, Lu Y, Xing X, Li Y, Huang Z, Zhong H, et al. Regulator of G-protein signaling 10 negatively regulates cardiac remodeling by blocking mitogen-activated protein kinase-extracellular signal-regulated protein kinase 1/2 signaling. Hypertension. 2016;67:86–98.

    Article  CAS  Google Scholar 

  31. Verma SK, Krishnamurthy P, Barefield D, Singh N, Gupta R, Lambers E, et al. Interleukin-10 treatment attenuates pressure overload-induced hypertrophic remodeling and improves heart function via signal transducers and activators of transcription 3-dependent inhibition of nuclear factor-kappaB. Circulation. 2012;126:418–29.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The study was supported by the National Natural Science Foundation of China (NSFC) Projects (Nos. 81800271 and 81670335) and the Natural Science Foundation of Hunan Province (No. 2019JJ50920).

Author information

Authors and Affiliations

  1. Department of Cardiology, The 3rd Xiangya Hospital of Central South University, Changsha, China

    Yuyan Wu, Yan Yang, Zhongshu Liang, Weihong Jiang & Xiaogang Li

  2. Department of Anesthesiology, The 3rd Xiangya Hospital of Central South University, Changsha, China

    Chengxuan Quan

Authors
  1. Yuyan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chengxuan Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yan Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhongshu Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weihong Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaogang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XL and WJ provided the general outline of the manuscript and designed the research study, XL and YW performed all experiments and wrote the manuscript, and CQ and YY verified and analyzed the raw data after the experiments. ZL provided assistance with our animal experiments.

Corresponding author

Correspondence to Xiaogang Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, Y., Quan, C., Yang, Y. et al. Renalase improves pressure overload-induced heart failure in rats by regulating extracellular signal-regulated protein kinase 1/2 signaling. Hypertens Res 44, 481–488 (2021). https://doi.org/10.1038/s41440-020-00599-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-020-00599-6

Keywords

This article is cited by

Search

Advanced search

Quick links