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Endothelin-converting enzyme-1 inhibition and renoprotection in end-stage renal disease

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Abstract

Endothelin is one of the most potent peptide vasoconstrictors thus far characterised. It is produced by the cleavage of its precursor big endothelin-1 by endothelin-converting enzyme-1 (ECE-1). The endothelin system which includes endothelin-1 (ET-1), ET receptors and ECE-1 is well characterised in the kidney and is known to play a key role in the pathogenesis of end-stage renal disease (ESRD). Therefore, inhibition of ECE-1 and antagonism of ET receptors represent potential therapeutic approaches for the treatment of ESRD. Here, we review the current literature on the localisation of ECE-1 in the normal kidney and how ECE-1 expression is altered in pathological conditions leading to ESRD. We also discuss the roles of neutral endopeptidase (NEP) and chymase in mediating the production of ET-1 in the kidney in ESRD. As such, we also discuss that complete inhibition of ET-1 production in the kidney requires the inhibition of ECE-1, NEP and chymase.

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References

  1. Abassi ZA, Golomb E, Bridenbaugh R, Keiser HR (1993) Metabolism of endothelin-1 and big endothelin-1 by recombinant neutral endopeptidase EC.3.4.24.11. Br J Pharmacol 109(4):1024–1028

    Article  PubMed  CAS  Google Scholar 

  2. Cooper ME GR, Allen TJ (1998) Lessons from animal diabetes VII. In: A S (ed) Experimental diabetic nephropathy. Harwood Academic Publishers GmbH, Amsterdam, pp 207–223

  3. Correa-Costa M, Azevedo H, Amano MT, Goncalves GM, Hyane MI, Cenedeze MA, Renesto PG, Pacheco-Silva A, Moreira-Filho CA, Camara NO (2012) Transcriptome analysis of renal ischemia/reperfusion injury and its modulation by ischemic pre-conditioning or hemin treatment. PLoS One 7(11):e49569. doi:10.1371/journal.pone.0049569

    Article  PubMed  CAS  Google Scholar 

  4. D'Orleans-Juste P, Houde M, Rae GA, Bkaily G, Carrier E, Simard E (2008) Endothelin-1 (1–31): from chymase-dependent synthesis to cardiovascular pathologies. Vasc Pharmacol 49(2–3):51–62. doi:10.1016/j.vph.2008.06.007

    Article  Google Scholar 

  5. Disashi T, Nonoguchi H, Iwaoka T, Naomi S, Nakayama Y, Shimada K, Tanzawa K, Tomita K (1997) Endothelin converting enzyme-1 gene expression in the kidney of spontaneously hypertensive rats. Hypertension 30(6):1591–1597

    Article  PubMed  CAS  Google Scholar 

  6. Feldman DL, Mogelesky TC, Chou M, Jeng AY (2000) Attenuation of puromycin aminonucleoside-induced glomerular lesions in rats by CGS 26303, a dual neutral endopeptidase/endothelin-converting enzyme inhibitor. J Cardiovasc Pharmacol 36(5 Suppl 1):S342–S345

    PubMed  CAS  Google Scholar 

  7. Frank K, Zeier M, Gross ML, Waldherr R, Ritz E, Amann K (2006) Comprehensive immunohistological analysis of the endothelin system in human kidney grafts. Nephrol Dial Transplant 21(5):1365–1372. doi:10.1093/ndt/gfk087

    Article  PubMed  CAS  Google Scholar 

  8. Harrison-Bernard LM, Berner PM, Zhang X, Husain A, Naqvi N (2012) Abstract 393: chymase: augmented renal tubular protein expression in diabetes hypertension 60 (3):A393 to A393

  9. Held HD, Raschak M, Uhlig S (1997) Rat big endothelin-1-induced bronchoconstriction and vasoconstriction in the isolated perfused rat lung: role of endothelin converting enzyme and neutral endopeptidase 24.11. Naunyn-Schmiedeberg's Archives of Pharmacology 355(5):619–624

    Article  PubMed  CAS  Google Scholar 

  10. Hocher B, Ziebig R, Altermann C, Krause R, Asmus G, Richter CM, Slowinski T, Sinha P, Neumayer HH (2003) Different impact of biomarkers as mortality predictors among diabetic and nondiabetic patients undergoing hemodialysis. J Am Soc Nephrol 14(9):2329–2337

    Article  PubMed  CAS  Google Scholar 

  11. Huang XR, Chen WY, Truong LD, Lan HY (2003) Chymase is upregulated in diabetic nephropathy: implications for an alternative pathway of angiotensin II-mediated diabetic renal and vascular disease. J Am Soc Nephrol 14(7):1738–1747

    Article  PubMed  CAS  Google Scholar 

  12. Ikebe M, Nonoguchi H, Nakayama Y, Tashima Y, Shimada K, Tanzawa K, Tomita K (2003) Regulation of endothelin-converting enzyme 1 in nephrotic syndrome in rats. Nephron Exp Nephrol 94(4):e137–e145. doi:72497

    Article  PubMed  CAS  Google Scholar 

  13. Ishimura E, Sterzel RB, Morii H, Kashgarian M (1992) Extracellular matrix protein: gene expression and synthesis in cultured rat mesangial cells. Nihon Jinzo Gakkai Shi 34(1):9–17

    PubMed  CAS  Google Scholar 

  14. Jandeleit-Dahm K, Allen TJ, Youssef S, Gilbert RE, Cooper ME (2000) Is there a role for endothelin antagonists in diabetic renal disease? Diabetes. Obes Metab 2(1):15–24

    Article  CAS  Google Scholar 

  15. Kanwar YS, Sun L, Xie P, Liu FY, Chen S (2011) A glimpse of various pathogenetic mechanisms of diabetic nephropathy. Annual Review of Pathology 6:395–423. doi:10.1146/annurev.pathol.4.110807.092150

    Article  PubMed  CAS  Google Scholar 

  16. Kerr MA, Kenny AJ (1974) The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J 137(3):477–488

    PubMed  CAS  Google Scholar 

  17. Khamaisi M, Dahan R, Hamed S, Abassi Z, Heyman SN, Raz I (2009) Role of protein kinase C in the expression of endothelin converting enzyme-1. Endocrinology 150(3):1440–1449. doi:10.1210/en.2008-0524

    Article  PubMed  CAS  Google Scholar 

  18. Khamaisi M, Raz I, Shilo V, Shina A, Rosenberger C, Dahan R, Abassi Z, Meidan R, Lecht S, Heyman SN (2008) Diabetes and radiocontrast media increase endothelin converting enzyme-1 in the kidney. Kidney Int 74(1):91–100. doi:10.1038/ki.2008.112

    Article  PubMed  CAS  Google Scholar 

  19. Korth P, Bohle RM, Corvol P, Pinet F (1999) Cellular distribution of endothelin-converting enzyme-1 in human tissues. J Histochem Cytochem 47(4):447–462

    Article  PubMed  CAS  Google Scholar 

  20. Kuruppu S, Tochon-Danguy N, Smith AI (2012) Protein kinase C recognition sites in the cytoplasmic domain of endothelin converting enzyme-1c. Biochem Biophys Res Commun 427(3):606–610. doi:10.1016/j.bbrc.2012.09.105

    Article  PubMed  CAS  Google Scholar 

  21. Matsumura Y, Kuro T, Kobayashi Y, Umekawa K, Ohashi N, Takaoka M (2000) Protective effect of SM-19712, a novel and potent endothelin converting enzyme inhibitor, on ischemic acute renal failure in rats. Japanese Journal of Pharmacology 84(1):16–24

    Article  PubMed  CAS  Google Scholar 

  22. Muller DN, Mullally A, Dechend R, Park JK, Fiebeler A, Pilz B, Loffler BM, Blum-Kaelin D, Masur S, Dehmlow H, Aebi JD, Haller H, Luft FC (2002) Endothelin-converting enzyme inhibition ameliorates angiotensin II-induced cardiac damage. Hypertension 40(6):840–846

    Article  PubMed  CAS  Google Scholar 

  23. Murphy LJ, Corder R, Mallet AI, Turner AJ (1994) Generation by the phosphoramidon-sensitive peptidases, endopeptidase-24.11 and thermolysin, of endothelin-1 and c-terminal fragment from big endothelin-1. Br J Pharmacol 113(1):137–142

    Article  PubMed  CAS  Google Scholar 

  24. Nambi P, Pullen M, Wu HL, Prabhakar U, Hersh L, Gellai M (1999) Down regulation of kidney neutral endopeptidase mRNA, protein and activity during acute renal failure: possible mechanism for ischemia-induced acute renal failure in rats? Mol Cell Biochem 197(1–2):53–59

    Article  PubMed  CAS  Google Scholar 

  25. Ortmann J, Nett PC, Celeiro J, Hofmann-Lehmann R, Tornillo L, Terracciano LM, Barton M (2006) Downregulation of renal endothelin-converting enzyme 2 expression in early autoimmune diabetes. Exp Biol Med (Maywood) 231(6):1030–1033

    CAS  Google Scholar 

  26. Ozawa Y, Hasegawa T, Tsuchiya K, Yoshizumi M, Tamaki T (2003) Effect of endothelin-1 (1–31) on the renal resistance vessels. The Journal of Medical Investigation: JMI 50(1–2):87–94

    PubMed  Google Scholar 

  27. Pupilli C, Romagnani P, Lasagni L, Bellini F, Misciglia N, Emoto N, Yanagisawa M, Rizzo M, Mannelli M, Serio M (1997) Localization of endothelin-converting enzyme-1 in human kidney. Am J Physiol 273(5 Pt 2):F749–F756

    PubMed  CAS  Google Scholar 

  28. Rabelink TJ, Stroes ES, Bouter KP, Morrison P (1998) Endothelin blockers and renal protection: a new strategy to prevent end-organ damage in cardiovascular disease? Cardiovasc Res 39(3):543–549

    Article  PubMed  CAS  Google Scholar 

  29. Russell FD, Coppell AL, Davenport AP (1998) In vitro enzymatic processing of radiolabelled big ET-1 in human kidney. Biochem Pharmacol 55(5):697–701

    Article  PubMed  CAS  Google Scholar 

  30. Sansoe G, Aragno M, Mastrocola R, Cutrin JC, Silvano S, Mengozzi G, Smedile A, Rosina F, Danni O, Rizzetto M (2006) Overexpression of kidney neutral endopeptidase (EC 3.4.24.11) and renal function in experimental cirrhosis. American Journal of Physiology Renal Physiology 290(6):F1337–1343. doi:10.1152/ajprenal.00435.2005

    Article  PubMed  CAS  Google Scholar 

  31. Sharma R, Prasad V, McCarthy ET, Savin VJ, Dileepan KN, Stechschulte DJ, Lianos E, Wiegmann T, Sharma M (2007) Chymase increases glomerular albumin permeability via protease-activated receptor-2. Mol Cell Biochem 297(1–2):161–169. doi:10.1007/s11010-006-9342-0

    Article  PubMed  CAS  Google Scholar 

  32. Simard E, Jin D, Takai S, Miyazaki M, Brochu I, D'Orleans-Juste P (2009) Chymase-dependent conversion of Big endothelin-1 in the mouse in vivo. J Pharmacol Exp Ther 328(2):540–548. doi:10.1124/jpet.108.142992

    Article  PubMed  CAS  Google Scholar 

  33. Smith AI, Lew RA, Thomas WG, Tochon-Danguy N (2006) Protein kinase C regulates the cell surface activity of endothelin-converting enzyme-1. Int J Pept Res Ther 12(3):291–295

    Article  PubMed  CAS  Google Scholar 

  34. Strait KA, Stricklett PK, Kohan JL, Miller MB, Kohan DE (2007) Calcium regulation of endothelin-1 synthesis in rat inner medullary collecting duct. American Journal of Physiology Renal Physiology 293(2):F601–606. doi:10.1152/ajprenal.00085.2007

    Article  PubMed  CAS  Google Scholar 

  35. System USRD (2010) USRDS 2010 Annual data report: atlas of chronic kidney disease and end-stage renal disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda

  36. Thone-Reinke C, Simon K, Richter CM, Godes M, Neumayer HH, Thormahlen D, Hocher B (2004) Inhibition of both neutral endopeptidase and endothelin-converting enzyme by SLV306 reduces proteinuria and urinary albumin excretion in diabetic rats. J Cardiovasc Pharmacol 44(Suppl 1):S76–S79

    Article  PubMed  Google Scholar 

  37. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332(6163):411–415

    Article  PubMed  CAS  Google Scholar 

  38. Yasuoka H, Yoshizumi M, Inui D, Okishima N, Houchi H, Kirima K, Oshita S, Kido H, Tamaki T (1999) Effect of endothelin-1(1–31) on intracellular free calcium in cultured human mesangial cells. Life Sci 65(22):PL267–PL272

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the funding from the National Health and Medical Research Council of Australia as well as the National Heart Foundation of Australia.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia

    Sanjaya Kuruppu & A. Ian Smith

  2. Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria, 3004, Australia

    Niwanthi W. Rajapakse

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  1. Sanjaya Kuruppu
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  3. A. Ian Smith
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Correspondence to Sanjaya Kuruppu.

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Kuruppu, S., Rajapakse, N.W. & Smith, A.I. Endothelin-converting enzyme-1 inhibition and renoprotection in end-stage renal disease. Pflugers Arch - Eur J Physiol 465, 929–934 (2013). https://doi.org/10.1007/s00424-013-1216-1

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  • DOI: https://doi.org/10.1007/s00424-013-1216-1

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