Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys


Autoři: Hanno Maassen aff001;  Koen D. W. Hendriks aff001;  Leonie H. Venema aff001;  Rob H. Henning aff003;  Sijbrand H. Hofker aff001;  Harry van Goor aff002;  Henri G. D. Leuvenink aff001;  Annemieke M. Coester aff001
Působiště autorů: Department of Surgery, UMCG, University of Groningen, Groningen, the Netherlands aff001;  Department of Pathology and Medical Biology, UMCG, University of Groningen, Groningen, the Netherlands aff002;  Department of Clinical Pharmacy and Pharmacology, UMCG, University of Groningen, Groningen, the Netherlands aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225152

Souhrn

Background

Since the start of organ transplantation, hypothermia-forced hypometabolism has been the cornerstone in organ preservation. Cold preservation showed to protect against ischemia, although post-transplant injury still occurs and further improvement in preservation techniques is needed. We hypothesize that hydrogen sulphide can be used as such a new preservation method, by inducing a reversible hypometabolic state in human sized kidneys during normothermic machine perfusion.

Methods

Porcine kidneys were connected to an ex-vivo isolated, oxygen supplemented, normothermic blood perfusion set-up. Experimental kidneys (n = 5) received a 85mg NaHS infusion of 100 ppm and were compared to controls (n = 5). As a reflection of the cellular metabolism, oxygen consumption, mitochondrial activity and tissue ATP levels were measured. Kidney function was assessed by creatinine clearance and fractional excretion of sodium. To rule out potential structural and functional deterioration, kidneys were studied for biochemical markers and histology.

Results

Hydrogen sulphide strongly decreased oxygen consumption by 61%, which was associated with a marked decrease in mitochondrial activity/function, without directly affecting ATP levels. Renal biological markers, renal function and histology did not change after hydrogen sulphide treatment.

Conclusion

In conclusion, we showed that hydrogen sulphide can induce a controllable hypometabolic state in a human sized organ, without damaging the organ itself and could thereby be a promising therapeutic alternative for cold preservation under normothermic conditions in renal transplantation.

Klíčová slova:

Creatinine – Histology – Ischemia – Kidneys – Mitochondria – Renal system – Renal transplantation – Oxygen consumption


Zdroje

1. Cavallo MC, Sepe V, Conte F, Abelli M, Ticozzelli E, Bottazzi A, et al. Cost-effectiveness of kidney transplantation from DCD in Italy. Transplant Proc 2014 Dec;46(10):3289–96. doi: 10.1016/j.transproceed.2014.09.146 25498039

2. Ojo AO, Hanson JA, Meier-Kriesche H, Okechukwu CN, Wolfe RA, Leichtman AB, et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001 Mar;12(3):589–97. 11181808

3. Kokkinos C, Antcliffe D, Nanidis T, Darzi AW, Tekkis P, Papalois V. Outcome of Kidney Transplantation From Nonheart-Beating Versus Heart-Beating Cadaveric Donors. Transplantation 2007 May 15;83(9):1193–9. doi: 10.1097/01.tp.0000261710.53848.51 17496535

4. Vinson A, Rose C, Kiberd B, Odutayo A, Kim S, Alwayn I et al. Factors Associated With Prolonged Warm Ischemia Time Among Deceased Donor Kidney Transplant Recipients. Transplantation Direct. 2018;4(5):e342. doi: 10.1097/TXD.0000000000000781 29796413

5. Slegtenhorst BR, Dor FJMF, Elkhal A, Rodriquez H, Yang X, Edtinger K, et al. Mechanisms and consequences of injury and repair in older organ transplants. Transplantation 2014 Jun 15;97(11):1091–9. doi: 10.1097/TP.0000000000000072 24646769

6. Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012;298:229–317. doi: 10.1016/B978-0-12-394309-5.00006-7 22878108

7. Garonzik‐Wang JM, Lonze BE, Ruck JM, Luo X, Massie AB, Melancon K, et al. Mitochondrial membrane potential and delayed graft function following kidney transplantation. Am J Transplant 2019; 19: 585–590. doi: 10.1111/ajt.15174 30408329

8. Lobb I, Jiang J, Lian D, Liu W, Haig A, Saha MN, et al. A. Hydrogen Sulfide Protects Renal Grafts Against Prolonged Cold Ischemia–Reperfusion Injury via Specific Mitochondrial Actions. Am J Transplant 2017; 17: 341–352 doi: 10.1111/ajt.14080 27743487

9. Snijder PM, van den Berg E, Whiteman M, Bakker SJ, Leuvenink HGD, van Goor H. Emerging Role of Gasotransmitters in Renal Transplantation. Am J Transplant 2013 13: 3067–3075. doi: 10.1111/ajt.12483 24266966

10. Dugbartey GJ, Bouma HR, Saha MN, Lobb I, Henning RH, Sener A: A Hibernation-Like State for Transplantable Organs: Is Hydrogen Sulfide Therapy the Future of Organ Preservation? Antioxid. Redox Signal 2018, 28, 1503–1515.

11. Blackstone E, Morrison M, Roth MB. H2S induces a suspended animation-like state in mice. Science 2005 Apr 22;308(5721):518. doi: 10.1126/science.1108581 15845845

12. Baumgart K, Radermacher P, Wagner F. Applying gases for microcirculatory and cellular oxygenation in sepsis: Effects of nitric oxide, carbon monoxide, and hydrogen sulfide. Curr Opin Anesthesiol 2009 22: 168–176.

13. Wetzel MD, Wenke JC: Mechanisms by which hydrogen sulfide attenuates muscle function following ischemia-reperfusion injury: effects on Akt signaling, mitochondrial function, and apoptosis. J Transl Med 2019 17(1):33. doi: 10.1186/s12967-018-1753-7 30665344

14. Bos EM, Leuvenink HG, Snijder PM, Kloosterhuis NJ, Hillebrands JL, Leemans JC, et al. Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J Am Soc Nephrol 2009 Sep;20(9):1901–5. doi: 10.1681/ASN.2008121269 19628669

15. Geng B, Chang L, Pan C, Qi Y, Zhao J, Pang Y, et al. Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun 2004 318(3):756–63. doi: 10.1016/j.bbrc.2004.04.094 15144903

16. Hosgood SA, Nicholson ML. Hydrogen sulphide ameliorates ischaemia-reperfusion injury in an experimental model of non-heart-beating donor kidney transplantation. Br J Surg. 2010 Feb;97(2):202–9. doi: 10.1002/bjs.6856 20034052

17. Hendriks KD, Maassen H, van Dijk PR, Henning RH, van Goor H, Hillebrands JL. Gasotransmitters in health and disease: a mitochondria centered view. Curr opin Pharmacol 2019 Apr;45:87–93. doi: 10.1016/j.coph.2019.07.001 31325730

18. Jensen AR, Drucker NA, Khaneki S, Ferkowicz MJ, Markel TA: Hydrogen sulfide improves intestinal recovery following ischemia by endothelial nitric oxide-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol 2017 312(5): G450–G456. doi: 10.1152/ajpgi.00444.2016 28280145

19. Li H, Zhang C, Sun W, Li L, Wu B, Bai S, et al: Exogenous hydrogen sulfide restores cardioprotection of ischemic post-conditioning via inhibition of mPTP opening in the aging cardiomyocytes. Cell Biosci 2015 30;5:43. doi: 10.1186/s13578-015-0035-9 26229588

20. Juriasingani S, Akbari M, Chan JY, Whiteman M, Sener A. H2S supplementation: A novel method for successful organ preservation at subnormothermic temperatures. Nitric Oxide 2018 Dec 1;81:57–66. doi: 10.1016/j.niox.2018.10.004 30393129

21. Dirkes MC, Milstein DMJ, Heger M, van Gulik TM. Absence of Hydrogen Sulfide-Induced Hypometabolism in Pigs: A Mechanistic Explanation in Relation to Small Nonhibernating Mammals. Eur Surg Res 2015;54(3–4):178–91. doi: 10.1159/000369795 25676197

22. Haouzi P, Notet V, Chenuel B, Chalon B, Sponne I, Ogier V, et al. H2S induced hypometabolism in mice is missing in sedated sheep. Respiratory Physiology & Neurobiology 2008 Jan 1;160(1):109–15.

23. Mooyaart EAQ, Gelderman ELG, Nijsten MW, de Vos R, Hirner JM, de Lange DW, et al. Outcome after hydrogen sulphide intoxication. Resuscitation 2016 Jun;103:1–6. doi: 10.1016/j.resuscitation.2016.03.012 26997477

24. Mahboub P, Ottens P, Seelen M, ‘t Hart N, van Goor H, Ploeg R, et al. Gradual rewarming with gradual increase in pressure during machine perfusion after cold static preservation reduces kidney ischemia reperfusion injury. PLoS One 2015;10(12):1–12.

25. Bon D, Chatauret N, Giraud S, Thuillier R, Favreau F, Hauet T. New strategies to optimize kidney recovery and preservation in transplantation. Nature Reviews Nephrology 2012 May 1;8(6):339–47. doi: 10.1038/nrneph.2012.83 22549229

26. Hendriks KDW, Lupi E, Hardenberg MC, Hoogstra-Berends F, Deelman LE, Henning RH. Differences in mitochondrial function and morphology during cooling and rewarming between hibernator and non-hibernator derived kidney epithelial cells. Scientific Reports 2017 Nov 14;7(1):15482. doi: 10.1038/s41598-017-15606-z 29138454

27. Hendriks KDW, Brüggenwirth IMA, Maassen H, Gerding A, Bakker B, Porte RJ, Henning RH, Leuvenink HGD. Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation. J. Trans Med. 2019 Aug 13;17(1):265.

28. Debout A, Foucher Y, Trebern-Launay K, Legendre C, Kreis H, Mourad G, et al. Each additional hour of cold ischemic time significantly increases the risk of graft failure and mortality following renal transplantation. Kidney Int 2015, 87: 343–349. doi: 10.1038/ki.2014.304 25229341

29. Meng G, Wang J, Xiao Y, Bai W, Xie L, Shan L, et al. GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats. J Biomed Res 2015 29: 203–213. doi: 10.7555/JBR.28.20140037 26060444

30. Lobb I., Mok A., Lan Z., Liu W., Garcia B., Sener A. Supplemental hydrogen sulphide protects transplant kidney function and prolongs recipient survival after prolonged cold ischaemia-reperfusion injury by mitigating renal graft apoptosis and inflammation BJU Int 2012 Dec;110(11 Pt C):E1187–95.

31. Sekijima M, Sahara H, Miki K, Villani V, Ariyoshi y, Iwanaga T, et al. Hydrogen sulfide prevents renal ischemia-reperfusion injury in CLAWN miniature swine. Journal of Surgical Research 2017 Nov;219:165–172. doi: 10.1016/j.jss.2017.05.123 29078877

32. Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, et al: 3-Mercaptopyruvate Sulfurtransferase Produces Hydrogen Sulfide and Bound Sulfane Sulfur in the Brain. Antioxid. Redox Signal 2009 11(4):703–14. doi: 10.1089/ARS.2008.2253 18855522

33. Teng H, Wu B, Zhao K, Yang G, Wu L, Wang R: Oxygen-sensitive mitochondrial accumulation of cystathionine β-synthase mediated by Lon protease. Proc Natl Acad Sci U S A 2013, 31:12679–84.

34. Khan lA.A, Schuler M.M, Prior M.G, Yong S, Coppock R.W, Florence L.Z, Lillie L.E. Effects of hydrogen sulfide exposure on lung mitochondrial respiratory chain enzymes in rats. Toxicol Appl Pharmacol. 1990 May;103(3):482–90. doi: 10.1016/0041-008x(90)90321-k 2160136

35. Kashfi K, Olson KR. Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras. Biochem Pharmacol 2013 Mar 1;85(5):689–703. doi: 10.1016/j.bcp.2012.10.019 23103569

36. Snijder PM, de Boer RA, Bos EM, van den Boorn JC, Ruifrok WPT, Vreeswijk-Baudoin I, et al. Gaseous Hydrogen Sulfide Protects against Myocardial Ischemia-Reperfusion Injury in Mice Partially Independent from Hypometabolism. PLoS One 2013 May 10;8(5):e63291. doi: 10.1371/journal.pone.0063291 23675473

37. Anzell AR, Maizy R, Przyklenk K, Sanderson TH. Mitochondrial Quality Control and Disease: Insights into Ischemia-Reperfusion Injury. Mol. Neurobiol 2018 Mar;55(3):2547–2564. doi: 10.1007/s12035-017-0503-9 28401475

38. Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 2001 Nov 1;20(21):6008–16. doi: 10.1093/emboj/20.21.6008 11689441

39. Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, et al. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322 (5901) (2008), pp. 587–590 doi: 10.1126/science.1162667 18948540

40. Koning AM, Frenay AS, Leuvenink HGD, van Goor H. Hydrogen sulfide in renal physiology, disease and transplantation–The smell of renal protection. Nitric Oxide 2015 Apr 30;46:37–49. doi: 10.1016/j.niox.2015.01.005 25656225


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2019 Číslo 11