THE IMPORTANCE OF POLYMORPHISMS OF REGULATORY AND CATALYTIC ANTIOXIDANT PROTEINS IN CHRONIC KIDNEY DISEASE
Keywords:
CKD, Nrf2, SOD2, GPX1, gene polymorphisms
Abstract
Both excessive production of reactive oxygen species (ROS) and impaired antioxidant function are found in patients with chronic kidney disease (CKD). Therefore, individual susceptibility towards CKD can be induced by functional variations of genes encoding antioxidant regulatory (nuclear factor erythroid 2–related factor 2 (Nrf2)) and catalytic (superoxide dismutase (SOD2) and glutathione peroxidase (GPX1)) proteins. Several types of single nucleotide polymorphisms (SNPs) have been found within the genes encoding these proteins, with Nrf2(-617C/A), SOD2(Ala16Val) and GPX1(Pro198Leu) conferring impaired catalytic activity. The most unexplored gene polymorphism in CKD susceptibility, progression and survival, with only two original studies published, is the Nrf2(-617C/A) polymorphism. The results of these studies showed that there was no individual impact of this polymorphism on the susceptibility towards end stage renal disease (ESRD) development, oxidative phenotype and mortality. However, Nrf2 had a significant role in ESRD risk and survival when combined with other antioxidant genes. The results regarding the impact of SOD2(Ala16Val) and GPX1(Pro198Leu) polymorphisms on either CKD or ESRD are still inconclusive. Namely, some studies showed that patients having variant SOD2(Val) or GPX1(Leu) allele were at increased risk of CKD development and progression, while other studies reported only weak or no association between these polymorphisms and CKD. Surprisingly, the only study that reported an association of GPX1 polymorphism on overall/cardiovascular survival in ESRD patients showed a significant impact of low activity GPX1(Leu/Leu) genotype on better survival. In this review, we comprehensively and critically appraise the literature on these polymorphisms related to oxidative stress in CKD patients in order to identify gaps and provide recommendations for further clinical research and translation. New developments in the field of antioxidant polymorphisms in CKD patients could lead to better stratification of CKD patients based on a prognostic antioxidant gene panel and provide a more personalised medicine approach for the need of antioxidant therapy in these patients.
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4. Thompson S, James M, Wiebe N, Hemmelgarn B, Manns B, Klarenbach S, et al. Cause of death in patients with reduced kidney function. J Am Soc Nephrol. 2015;26(10):2504–11.
5. Fiorillo C, Oliviero C, Rizzuti G, Nediani C, Pacini A, Nassi P. Oxidative stress and antioxidant defenses in renal patients receiving regular haemodialysis. Clin Chem Lab Med. 1998;36(3):149–53.
6. Vaziri ND. Oxidative stress in uremia: nature, mechanisms, and potential consequences. In: Seminars in nephrology. Elsevier; 2004. p. 469–73.
7. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62(5):1524–38.
8. Oberg BP, Mcmenamin E, Lucas FL, Mcmonagle E, Morrow J, Ikizler TA, et al. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney Int. 2004 Mar;65(3):1009–16.
9. Vaziri ND, Oveisi F, Ding Y. Role of increased oxygen free radical activity in the pathogenesis of uremic hypertension. Kidney Int. 1998;53(6):1748–54.
10. Sies H. Oxidative stress: from basic research to clinical application. Am J Med. 1991;91(3):S31–8.
11. Sies H. Oxidative stress: eustress and distress in redox homeostasis. In: Stress: physiology, biochemistry, and pathology. Elsevier; 2019. p. 153–63.
12. Massy ZA, Ceballos I, Chadefaux-Vekemens B, Nguyen-Khoa T, Descamps-Latscha B, Drüeke TB, et al. Homocyst (e) ine, oxidative stress, and endothelium function in uremic patients. Kidney Int. 2001;59(S78):S243.
13. Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal. 2007;9(12):2277–94.
14. Chin MP, Reisman SA, Bakris GL, O’grady M, Linde PG, McCullough PA, et al. Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Am J Nephrol. 2014;39(6):499–508.
15. Ward RA, McLeish KR. Polymorphonuclear leukocyte oxidative burst is enhanced in patients with chronic renal insufficiency. J Am Soc Nephrol. 1995;5(9):1697–702.
16. Galvan DL, Green NH, Danesh FR. The hallmarks of mitochondrial dysfunction in chronic kidney disease. Kidney Int. 2017;92(5):1051–7.
17. Laher I. Systems biology of free radicals and antioxidants. Springer; 2014.
18. Nguyen AT, Lethias C, Zingraff J, Herbelin A, Naret C, Descamps-Latscha B. Hemodialysis membrane-induced activation of phagocyte oxidative metabolism detected in vivo and in vitro within microamounts of whole blood. Kidney Int. 1985;28(2):158–67.
19. Tbahriti HF, Kaddous A, Bouchenak M, Mekki K. Effect of different stages of chronic kidney disease and renal replacement therapies on oxidant-antioxidant balance in uremic patients. Biochem Res Int. 2013;2013.
20. Girelli D, Olivieri O, Stanzial AM, Azzini M, Lupo A, Bernich P, et al. Low platelet glutathione peroxidase activity and serum selenium concentration in patients with chronic renal failure: relations to dialysis treatments, diet and cardiovascular complications. Clin Sci. 1993;84(6):611–7.
21. Ceballos-Picot I, Witko-Sarsat V, Merad-Boudia M, Nguyen AT, Thévenin M, Jaudon MC, et al. Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure. Free Radic Biol Med. 1996;21(6):845–53.
22. Sung C-C, Hsu Y-C, Chen C-C, Lin Y-F, Wu C-C. Oxidative stress and nucleic acid oxidation in patients with chronic kidney disease. Oxid Med Cell Longev. 2013;2013.
23. Daenen K, Andries A, Mekahli D, Van Schepdael A, Jouret F, Bammens B. Oxidative stress in chronic kidney disease. Pediatr Nephrol. 2019;34(6):975–91.
24. Ward RA, Ouseph R, Mcleish KR. Effects of high-flux hemodialysis on oxidant stress. Kidney Int. 2003;63(1):353–9.
25. Jankowska M, Rutkowski B, Dębska-Ślizień A. Vitamins and microelement bioavailability in different stages of chronic kidney disease. Nutrients. 2017;9(3):282.
26. Davies KJ. Protein damage and degradation by oxygen radicals. I. general aspects. J Biol Chem. 1987;262(20):9895–901.
27. Wolff SP, Garner A, Dean RT. Free radicals, lipids and protein degradation. Trends Biochem Sci. 1986;11(1):27–31.
28. Imlay JA, Linn S. DNA damage and oxygen radical toxicity. Science (80- ). 1988;240(4857):1302–9.
29. Mimić-Oka J, Savić-Radojević A, Plješa-Ercegovac M, Opačić M, Simić T, Dimković N, et al. Evaluation of oxidative stress after repeated intravenous iron supplementation. Ren Fail. 2005;27(3):345–51.
30. Choi B, Kang K-S, Kwak M-K. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules. 2014;19(8):12727–59.
31. Tucker PS, Dalbo VJ, Han T, Kingsley MI. Clinical and research markers of oxidative stress in chronic kidney disease. Biomarkers. 2013;18(2):103–15.
32. Grieve DJ, Pljesa-Ercegovac M, Savic-Radojevic A, Damjanovic T, Dimkovic N, McClements L, et al. Research Article GSTM1 Modulates Expression of Endothelial Adhesion Molecules in Uremic Milieu. 2021;
33. Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H, Lanken PN, et al. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J. 2007;21(9):2237–46.
34. Sutton A, Khoury H, Prip-Buus C, Cepanec C, Pessayre D, Degoul F. The Ala16Val genetic dimorphism modulates the import of human manganese superoxide dismutase into rat liver mitochondria. Pharmacogenet Genomics. 2003;13(3):145–57.
35. Zheikova T V, Golubenko M V, Buikin S V, Botkina OY, Makeeva OA, Lezhnev AA, et al. Glutathione peroxidase 1 (GPX1) single nucleotide polymorphism Pro198→ Leu: Association with life span and coronary artery disease. Mol Biol. 2012;46(3):433–7.
36. Hamanishi T, Furuta H, Kato H, Doi A, Tamai M, Shimomura H, et al. Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases in Japanese type 2 diabetic patients. Diabetes. 2004;53(9):2455–60.
37. Li W, Khor TO, Xu C, Shen G, Jeong W-S, Yu S, et al. Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76(11):1485–9.
38. Tonelli C, Chio IIC, Tuveson DA. Transcriptional regulation by Nrf2. Antioxid Redox Signal. 2018;29(17):1727–45.
39. Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul. 2006;46:113–40.
40. Ihoriya C, Satoh M, Komai N, Sasaki T, Kashihara N. Nuclear factor erythroid 2-related factor 2 is activated by rosuvastatin via p21cip1 upregulation in endothelial cells. Biochem Pharmacol (Los Angel). 2014;4(157):501–2167.
41. Stockler-Pinto MB, Fouque D, Soulage CO, Croze M, Mafra D. Indoxyl sulfate and p-cresyl sulfate in chronic kidney disease. Could these toxins modulate the antioxidant Nrf2-Keap1 pathway? J Ren Nutr. 2014;24(5):286–91.
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