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Renalase alleviates salt-induced kidney necroptosis and inflammation

Hypertension Research volume 47, pages 2811–2825 (2024)Cite this article

Abstract

Recent evidence suggests that necroptosis may contribute to the development of kidney injury. Renalase is a novel secretory protein that exerts potent prosurvival and anti-inflammatory effects. We hypothesized that renalase could protect the kidney from salt-induced injury by modulating necroptosis. High salt and renalase treatments were administered to Dahl salt-sensitive (SS) rats, renalase knockout (KO) mice, and HK-2 cells. Furthermore, a cohort of 514 eligible participants was utilized to investigate the association between single nucleotide polymorphisms (SNPs) in the genes RIPK1, RIPK3, and MLKL, and the risk of subclinical renal damage (SRD) over 14 years. A high-salt diet significantly increased the expression of key components of necroptosis, namely RIPK1, RIPK3, and MLKL, as well as the release of inflammatory factors in SS rats. Treatment with recombinant renalase reduced both necroptosis and inflammation. In renalase KO mice, salt-induced kidney injury was more severe than in wild-type mice, but supplementation with renalase attenuated the kidney injury. In vitro experiments with HK-2 cells revealed high salt increased necroptosis and inflammation. Renalase exhibited a dose-dependent decrease in salt-induced necroptosis, and this cytoprotective effect was negated by the knockdown of PMCA4b, which is the receptor of renalase. Furthermore, the cohort study showed that SNP rs3736724 in RIPK1 and rs11640974 in MLKL were significantly associated with the risk of SRD over 14 years. Our analysis shows that necroptosis plays a significant role in the development of salt-induced kidney injury and that renalase confers its cytoprotective effects by inhibiting necroptosis and inflammation.

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References

  1. Weinberger MH. Salt sensitivity of blood pressure in humans. Hypertension. 1996;27:481–90.

    Article  CAS  PubMed  Google Scholar 

  2. Strazzullo P, D’Elia L, Kandala NB, Cappuccio FP. Salt intake, stroke, and cardiovascular disease: meta-analysis of prospective studies. Bmj. 2009;339:b4567.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Malta D, Petersen KS, Johnson C, Trieu K, Rae S, Jefferson K, et al. High sodium intake increases blood pressure and risk of kidney disease. From the Science of Salt: A regularly updated systematic review of salt and health outcomes (August 2016 to March 2017). J Clin Hypertens (Greenwich). 2018;20:1654–65.

    Article  CAS  PubMed  Google Scholar 

  4. du Cailar G, Mimran A. Non-pressure-related effects of dietary sodium. Curr Hypertens Rep. 2009;11:12–7.

    Article  PubMed  Google Scholar 

  5. Yu HC, Burrell LM, Black MJ, Wu LL, Dilley RJ, Cooper ME, et al. Salt induces myocardial and renal fibrosis in normotensive and hypertensive rats. Circulation. 1998;98:2621–8.

    Article  CAS  PubMed  Google Scholar 

  6. Sanders PW. Salt intake, endothelial cell signaling, and progression of kidney disease. Hypertension. 2004;43:142–6.

    Article  CAS  PubMed  Google Scholar 

  7. Shen B, Hagiwara M, Yao YY, Chao L, Chao J. Salutary effect of kallistatin in salt-induced renal injury, inflammation, and fibrosis via antioxidative stress. Hypertension. 2008;51:1358–65.

    Article  CAS  PubMed  Google Scholar 

  8. Wang Y, Mu JJ, Liu FQ, Ren KY, Xiao HY, Yang Z, et al. Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure. Braz J Med Biol Res. 2014;47:223–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Campese VM, Parise M, Karubian F, Bigazzi R. Abnormal renal hemodynamics in black salt-sensitive patients with hypertension. Hypertension. 1991;18:805–12.

    Article  CAS  PubMed  Google Scholar 

  10. Bihorac A, Tezcan H, Ozener C, Oktay A, Akoglu E. Association between salt sensitivity and target organ damage in essential hypertension. Am J Hypertens. 2000;13:864–72.

    Article  CAS  PubMed  Google Scholar 

  11. Galluzzi L, Kepp O, Chan FK, Kroemer G. Necroptosis: mechanisms and relevance to disease. Annu Rev Pathol. 2017;12:103–30.

    Article  CAS  PubMed  Google Scholar 

  12. Mulay SR, Desai J, Kumar SV, Eberhard JN, Thomasova D, Romoli S, et al. Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis. Nat Commun. 2016;7:10274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2014;16:55–65.

    Article  CAS  PubMed  Google Scholar 

  14. Linkermann A, Bräsen JH, Himmerkus N, Liu S, Huber TB, Kunzendorf U, et al. Rip1 (receptor-interacting protein kinase 1) mediates necroptosis and contributes to renal ischemia/reperfusion injury. Kidney Int. 2012;81:751–61.

    Article  CAS  PubMed  Google Scholar 

  15. Ye L, Pang W, Huang Y, Wu H, Huang X, Liu J, et al. Lansoprazole promotes cisplatin-induced acute kidney injury via enhancing tubular necroptosis. J Cell Mol Med. 2021;25:2703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Linkermann A, Heller JO, Prókai A, Weinberg JM, De Zen F, Himmerkus N, et al. The RIP1-kinase inhibitor necrostatin-1 prevents osmotic nephrosis and contrast-induced AKI in mice. J Am Soc Nephrol. 2013;24:1545–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hanus J, Anderson C, Sarraf D, Ma J, Wang S. Retinal pigment epithelial cell necroptosis in response to sodium iodate. Cell Death Discov. 2016;2:16054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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  PubMed  PubMed Central  Google Scholar 

  19. Vijayakumar A, Mahapatra NR. Renalase: a novel regulator of cardiometabolic and renal diseases. Hypertens Res. 2022;45:1582–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang Y, Chen C, Hu GL, Chu C, Zhang XY, Du MF, et al. Associations of Renalase With Blood Pressure and Hypertension in Chinese Adults. Front Cardiovasc Med. 2022;9:800427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Buraczynska M, Zukowski P, Buraczynska K, Mozul S, Ksiazek A. Renalase gene polymorphisms in patients with type 2 diabetes, hypertension and stroke. Neuromolecular Med. 2011;13:321–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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  PubMed  PubMed Central  Google Scholar 

  23. Lee HT, Kim JY, Kim M, Wang P, Tang L, Baroni S, et al. Renalase protects against ischemic AKI. J Am Soc Nephrol. 2013;24:445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yin J, Liu X, Zhao T, Liang R, Wu R, Zhang F, et al. A protective role of renalase in diabetic nephropathy. Clin Sci (Lond). 2020;134:75–85.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao B, Zhao Q, Li J, Xing T, Wang F, Wang N. Renalase protects against contrast-induced nephropathy in Sprague-Dawley rats. PLoS One. 2015;10:e0116583.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Wang Y, Jia H, Gao WH, Zou T, Yao S, Du MF, et al. Associations of plasma PAPP-A2 and genetic variations with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. J Hypertens. 2021;39:1817–25.

    Article  CAS  PubMed  Google Scholar 

  27. Wang Y, Zhou Q, Gao WH, Yan Y, Chu C, Chen C, et al. Association of plasma cyclooxygenase-2 levels and genetic polymorphisms with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults. J Hypertens. 2020;38:1745–54.

    Article  CAS  PubMed  Google Scholar 

  28. Wang Y, Du MF, Yao S, Zou T, Zhang XY, Hu GL, et al. Associations of serum uromodulin and its genetic variants with blood pressure and hypertension in chinese adults. Front Cardiovasc Med. 2021;8:710023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zou T, Yao S, Du MF, Mu JJ, Chu C, Hu GL, et al. Associations of corin genetic polymorphisms with salt sensitivity, blood pressure changes, and hypertension incidence in Chinese adults. J Clin Hypertens (Greenwich). 2021;23:2115–23.

    Article  CAS  PubMed  Google Scholar 

  30. Wang D, Wang Y, Liu FQ, Yuan ZY, Mu JJ. High salt diet affects renal sodium excretion and ERRα expression. Int J Mol Sci. 2016;17:480.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Cao Y, Fang Y, Mu J, Liu X. High salt medium activates RhoA/ROCK and downregulates eNOS expression via the upregulation of ADMA. Mol Med Rep. 2016;14:606–12.

    Article  CAS  PubMed  Google Scholar 

  32. Khoury MK, Gupta K, Franco SR, Liu B. Necroptosis in the pathophysiology of disease. Am J Pathol. 2020;190:272–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang Y, Zhao P, Chu C, Du MF, Zhang XY, Zou T, et al. Associations of long-term visit-to-visit blood pressure variability with subclinical kidney damage and albuminuria in adulthood: a 30-year prospective cohort study. Hypertension. 2022;79:1247–56.

    Article  CAS  PubMed  Google Scholar 

  34. Mulè G, Castiglia A, Cusumano C, Scaduto E, Geraci G, Altieri D, et al. Subclinical kidney damage in hypertensive patients: a renal window opened on the cardiovascular system. Focus on microalbuminuria. Adv Exp Med Biol. 2017;956:279–306.

    Article  PubMed  Google Scholar 

  35. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281–357.

    Article  CAS  PubMed  Google Scholar 

  36. Wu XN, Yang ZH, Wang XK, Zhang Y, Wan H, Song Y, et al. Distinct roles of RIP1-RIP3 hetero- and RIP3-RIP3 homo-interaction in mediating necroptosis. Cell Death Differ. 2014;21:1709–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–27.

    Article  CAS  PubMed  Google Scholar 

  38. Wang L, Velazquez H, Chang J, Safirstein R, Desir GV. Identification of a receptor for extracellular renalase. PLoS One. 2015;10:e0122932.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Linkermann A, Bräsen JH, Darding M, Jin MK, Sanz AB, Heller JO, et al. Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc Natl Acad Sci USA. 2013;110:12024–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xu CH, Wang JN, Suo XG, Ji ML, He XY, Chen X, et al. RIPK3 inhibitor-AZD5423 alleviates acute kidney injury by inhibiting necroptosis and inflammation. Int Immunopharmacol. 2022;112:109262.

    Article  CAS  PubMed  Google Scholar 

  41. Wang L, Velazquez H, Moeckel G, Chang J, Ham A, Lee HT, et al. Renalase prevents AKI independent of amine oxidase activity. J Am Soc Nephrol. 2014;25:1226–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Guo X, Xu L, Velazquez H, Chen TM, Williams RM, Heller DA, et al. Kidney-targeted renalase agonist prevents cisplatin-induced chronic kidney disease by inhibiting regulated necrosis and inflammation. J Am Soc Nephrol. 2022;33:342–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu Y, Wang L, Deng D, Zhang Q, Liu W. Renalase protects against renal fibrosis by inhibiting the activation of the ERK signaling pathways. Int J Mol Sci. 2017;18:855.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wu Y, Wang L, Wang X, Wang Y, Zhang Q, Liu W. Renalase contributes to protection against renal fibrosis via inhibiting oxidative stress in rats. Int Urol Nephrol. 2018;50:1347–54.

    Article  CAS  PubMed  Google Scholar 

  45. Yan J, Wan P, Choksi S, Liu ZG. Necroptosis and tumor progression. Trends Cancer. 2022;8:21–7.

    Article  CAS  PubMed  Google Scholar 

  46. Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019;20:19–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Tiegs G, Horst AK. TNF in the liver: targeting a central player in inflammation. Semin Immunopathol. 2022;44:445–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Philipp S, Sosna J, Adam D. Cancer and necroptosis: friend or foe? Cell Mol Life Sci. 2016;73:2183–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Bode K, MacDonald T, Stewart T, Mendez B, Cai EP, Morrow N, et al. Protective renalase deficiency in β-cells shapes immune metabolism and function in autoimmune diabetes. Diabetes. 2023;72:1127–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kolodecik TR, Reed AM, Date K, Shugrue CA, Patel V, Chung SL, et al. The serum protein renalase reduces injury in experimental pancreatitis. J Biol Chem. 2017;292:21047–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mohamed TMA, Abou-Leisa R, Stafford N, Maqsood A, Zi M, Prehar S, et al. The plasma membrane calcium ATPase 4 signalling in cardiac fibroblasts mediates cardiomyocyte hypertrophy. Nat Commun. 2016;7:11074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang Y, Liu FQ, Wang D, Mu JJ, Ren KY, Guo TS, et al. Effect of salt intake and potassium supplementation on serum renalase levels in Chinese adults: a randomized trial. Medicine (Baltimore). 2014;93:e44.

    Article  CAS  PubMed  Google Scholar 

  53. Sizova D, Velazquez H, Sampaio-Maia B, Quelhas-Santos J, Pestana M, Desir GV. Renalase regulates renal dopamine and phosphate metabolism. Am J Physiol Renal Physiol. 2013;305:F839–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang S, Lu X, Yang J, Wang H, Chen C, Han Y, et al. Regulation of renalase expression by D5 dopamine receptors in rat renal proximal tubule cells. Am J Physiol Renal Physiol. 2014;306:F588–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China No. 82070437 (J.-J.M.), Natural Science Basic Research Program of Shaanxi Province (2021JM-257, 2021JM-588), Key R&D Projects in Shaanxi Province Grant No. 2023-ZDLSF-50, Basic-Clinical Integration Innovation Project in Medicine of Xi’an Jiaotong University (YXJLRH2022009), Xi'an Science and Technology Program Project (No. 24YXYJ0141), Institutional Foundation of the First Affiliated Hospital of Xi’an Jiaotong University No. 2022MS-36, 2021ZXY-14 (Y.W.), Fundamental Research Funds for the Central Universities (No. xzy012023113), the Chinese Academy of Medical Sciences & Peking Union Medical College (2017-CXGC03-2) and International Joint Research Center for Cardiovascular Precision Medicine of Shaanxi Province (2020GHJD-14).

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  1. These authors contributed equally: Yang Wang, Hao Jia.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China

    Yang Wang, Hao Jia, Ke Gao, Ming-Fei Du, Chao Chu, Dan Wang, Qiong Ma, Gui-Lin Hu, Xi Zhang, Yue Sun, Zi-Yue Man & Jian-Jun Mu

  2. Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi’an, China

    Yang Wang, Hao Jia, Ming-Fei Du, Chao Chu, Dan Wang, Gui-Lin Hu, Xi Zhang, Yue Sun & Jian-Jun Mu

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Wang, Y., Jia, H., Gao, K. et al. Renalase alleviates salt-induced kidney necroptosis and inflammation. Hypertens Res 47, 2811–2825 (2024). https://doi.org/10.1038/s41440-024-01814-4

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