Fonksiyonel Yağ Asitlerinin (Gla, Omega-3 ve Omega-6) Renal Koruyucu Etkileri
Özet
Bu kitap bölümünde, gama-linolenik asit (GLA), omega-3 ve omega-6 gibi fonksiyonel çoklu doymamış yağ asitlerinin (PUFA) böbrek sağlığı üzerindeki renal koruyucu etkileri deneysel modeller, moleküler mekanizmalar ve klinik perspektifler ışığında incelenmektedir. Böbrekler yüksek metabolik aktiviteleri nedeniyle ilaç, ağır metal ve çevresel kirleticilerin yol açtığı nefrotoksisiteye karşı oldukça hassastır. Bu hasarların patofizyolojisinde oksidatif stres, enflamasyon, mitokondriyal disfonksiyon ve ferropitozis gibi hücresel ölüm yolakları merkezi rol oynamaktadır. Çalışmada, omega-3 yağ asitlerinin (EPA ve DHA) pro-enflamatuvar mediyatörleri baskılayıp Nrf2 yolunu aktive ederek antioksidan sistemleri güçlendirdiği; TGF-β/Smad sinyalini inhibe ederek renal fibrozisi yavaşlattığı aktarılmaktadır. Bir omega-6 türevi olan GLA'nın ise DGLA ve antienflamatuvar PGE1 dönüşümü üzerinden klasik "omega-6 pro-enflamatuardır" genellemesini yıkarak doku hasarını ve lipit peroksidasyonunu azalttığı belirtilmektedir. Son olarak, omega-6/omega-3 oranının dengelenmesinin (özellikle 1-4:1 aralığının) renal homeostaz, proteinürinin azaltılması ve GFR'nin korunması açısından kritik bir beslenme stratejisi olduğu vurgulanmaktadır.
This book chapter evaluates the renal protective effects of functional polyunsaturated fatty acids (PUFAs), including gamma-linolenic acid (GLA), omega-3, and omega-6, through experimental nephrotoxicity models, molecular mechanisms, and clinical-translational perspectives. Due to their high metabolic rate, kidneys are highly susceptible to toxicity induced by heavy metals and therapeutic agents. Key pathophysiological processes driving renal damage involve oxidative stress, inflammation, mitochondrial dysfunction, and regulated cell death pathways such as ferroptosis and pyroptosis. The chapter highlights that omega-3 fatty acids (EPA and DHA) suppress pro-inflammatory cytokines via NF-kB inhibition, activate the Nrf2 pathway to boost antioxidant defenses, and mitigate renal fibrosis by suppressing TGF-β/Smad signaling. Concurrently, GLA, an omega-6 fatty acid, challenges the typical pro-inflammatory assumption of its class by converting into anti-inflammatory PGE1, thereby reducing lipid peroxidation and tubular degeneration. Ultimately, managing the dietary omega-6/omega-3 ratio (optimally 1-4:1) stands out as a crucial nutritional strategy to alleviate proteinuria and maintain GFR.
Referanslar
Vaziri ND, Norris K. Lipit disorders and their relevance to outcomes in chronic kidney disease. Blood Purif. 2011;31(1–3):189–96.doi:10.1159/000321845
Perazella MA. Pharmacology behind common drug nephrotoxicities. Clinical Journal of the American Society of Nephrology. 2018;13(12):1897–908.doi:10.2215/CJN.00150118
Vaidya VS, Ferguson MA, Bonventre J V. Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol. 2008;48(1):463–93. doi: 10.1146/annurev.pharmtox.48.113006.094615
Dragoș D, Enache II, Manea MM. Oxidative Stress and Nutritional Antioxidants in Renal Diseases: A Narrative Review. Antioxidants. 2025;14(7):757. doi:10.3390/antiox14070757
Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, et al. Chronic kidney disease: global dimension and perspectives. The lancet.2013;382(9888):260–72. doi: 10.1016/S0140-6736 (13)60687-X
Hoste EAJ, Kellum JA, Selby NM, Zarbock A, Palevsky PM, Bagshaw SM, et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018;14(10):607–25.doi:10.1038/s41581-018-0052-0
Calder PC. Polyunsaturated fatty acids and inflammatory processes: New twists in an old tale. Biochimie. 2009;91(6):791–5. doi:10.1016/ j.biochi.2009.01.008
Sureshbabu A, Ryter SW, Choi ME. Oxidative stress and autophagy: crucial modulators of kidney injury. Redox Biol. 2015;4:208–14. doi.org/10.1016/j.redox.2015.01.001
Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomedicine & pharmacotherapy. 2003;57(3–4):145–55. https://doi.org/10.1016/S0753-3322(03)00043-X
Tchounwou PB, Yedjou CG, Patlolla AK, Sutton DJ. Heavy metal toxicity and the environment. Molecular, clinical and environmental toxicology: volume 3: environmental toxicology. 2012;133–64. doi: 10.1007/978-3-7643-8340-4_6
Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int. 2008;73(9):994–1007. doi: 10.1038/sj.ki.5002786
Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int. 2011;79(1):33–45. https://doi.org/10.1038/ki.2010.337
Vaziri ND. Roles of oxidative stress and antioxidant therapy in chronic kidney disease and hypertension. Curr Opin Nephrol Hypertens. 2004;13(1):93–9. DOI:10.1097/00041552-200401000-00013
Flora G, Gupta D, Tiwari A. Toxicity of lead: a review with recent updates. Interdiscip Toxicol. 2012;5(2):47. doi: 10.2478/v10102-012-0009-2
Simopoulos AP. Omega-6/omega-3 essential fatty acid ratio and chronic diseases. Food reviews international. 2004;20(1):77–90. https://doi.org/10.1081/FRI-120028831
Kris-Etherton PM, Harris WS, Appel LJ. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol. 2003;23(2):151–2. https://doi.org/10.1161/01.ATV.0000057393.97337.A
Swanson D, Block R, Mousa SA. Omega-3 fatty acids EPA and DHA: health benefits throughout life. Advances in nutrition. 2012;3(1):1–7. doi:10.1001/jamacardio.2017.5205
Fan YY, Chapkin RS. Importance of dietary γ-linolenic acid in human health and nutrition. J Nutr. 1998;128(9):1411–4. doi:10.1093/jn /128.9.1411
Horrobin DF. Nutritional and medical importance of gamma-linolenic acid. Prog Lipit Res. 1992;31(2):163–94. doi:10.1016/0163-7827(92)90008-7
Yang Z, Li H, Wu H yan, Zhou Y, Du J xue, Hu Z xue. Omega-3 polyunsaturated fatty acids alleviate hyperuricemic nephropathy by inhibiting renal pyroptosis through GPR120. Biochem Pharmacol. 2024;230:116575. doi: 10.1016/j.bcp.2024.116575
Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans. 2017;45(5):1105–15. doi:10.1042/BST20160474
Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83(6):1029–41. doi:10.1038/ ki.2012.439
Zhang Z, Liu Y, Feng W, Mao P, Yang J, Zhao Z, et al. Omega-3 polyunsaturated fatty acids protect against cisplatin-induced nephrotoxicity by activating the Nrf2 signaling pathway. Int J Biol Macromol.2024;282:137457. doi:10.1016/j.ijbiomac.2024.137457
Simopoulos AP. An increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity. Nutrients. 2016;8(3):128. doi: 10.3390/nu8030128
Calder PC. Functional roles of fatty acids and their effects on human health. Journal of parenteral and enteral nutrition. 2015;39:18S-32S. doi: 10.1177/0148607115595980
Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomedicine & pharmacotherapy. 2002;56(8):365–79. doi:10.1016/S0753-3322(02)00253-6
Calder PC. Omega‐3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology? Br J Clin Pharmacol. 2013;75(3):645–62.doi: 10.1111/j.1365-2125.2012.04374.x
Hasan HM, Althanoon Z. Overview of Essential Fatty Acids: Types and Applications. doi: 10.21522/TIJPH.2013.13.02.Art047
Silva JR, Burger B, Kühl CMC, Candreva T, Dos Anjos MBP, Rodrigues HG. Wound healing and omega‐6 fatty acids: From inflammation to repair. Mediators Inflamm. 2018;2018(1):2503950. doi: 10.1155/2018/2503950
Patterson E, Wall R, Fitzgerald GF, Ross RP, Stanton C. Health implications of high dietary omega‐6 polyunsaturated fatty acids. J Nutr Metab. 2012;2012(1):539426. doi: 10.1155/2012/539426
Ilich JZ, Kelly OJ, Kim Y, Spicer MT. Low-grade chronic inflammation perpetuated by modern diet as a promoter of obesity and osteoporosis. Arh Hig Rada Toksikol. 2014;65(2):139–47. doi: 10.2478/10004-1254-65-2014-2541
Das UN. Essential fatty acids: biochemistry, physiology and pathology. Biotechnology Journal: Healthcare Nutrition Technology. 2006;1(4):420–39. doi: 10.1002/biot.200600012
Christie WW, Han X. Lipit analysis: isolation, separation, identification and lipitomic analysis. Elsevier; 2010.
Calder PC. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipits. 2015;1851(4):469–84.doi: 10.1016/j.bbalip.2014.08.010
Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, et al. Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76(11):1485–9. doi: 10.1016/j.bcp.2008.07.024
Farías JG, Carrasco-Pozo C, Carrasco Loza R, Sepulveda N, Alvarez P, Quezada M, et al. Polyunsaturated fatty acid induces cardioprotection against ischemia-reperfusion through the inhibition of NF-kappaB and induction of Nrf2. Exp Biol Med. 2017;242(10):1104–14. doi: 10.1177/1535370217709414
Han S, Choi H, Park H, Kim JJ, Lee EJ, Ham YR, et al. Omega-3 fatty acids attenuate renal fibrosis via AMPK-mediated autophagy flux activation. Biomedicines. 2023;11(9):2553. doi:10.3390/biomedicines 11092553
Xu J, Feng ZP, Peng HY, Fu P. Omega-3 polyunsaturated fatty acids alleviate adenine-induced chronic renal failure via regulating ROS production and TGF-β/SMAD pathway. Eur Rev Med Pharmacol Sci. 2021;25(12).doi: 10.26355/eurrev_202111_27221
Duysak L, Yüce N, Kılıç AF, Erkuş E. The effects of hemodialysis on oxidative stress in patients with chronic kidney failure. Health Sciences Quarterly. 2025;5(3):289–98.doi: 10.26900/hsq.2750
Aslankoç R, Demirci D, İnan Ü, Yıldız M, Öztürk A, Çetin M, et al. Oksidatif stres durumunda antioksidan enzimlerin rolü-Süperoksit dismutaz (SOD), katalaz (CAT) ve glutatyon peroksidaz (GPX). Medical Journal of Süleyman Demirel University. 2019;26(3):362–9. doi: 10.17343/sdutfd.566969
Lin YL, Wang CL, Liu KL, Yeh CN, Chiang TI. Omega-3 fatty acids improve chronic kidney disease—associated pruritus and inflammation. Medicina. 2022;58(6):796. doi: 10.3390/medicina 58060796
Matoba K, Takeda Y, Nagai Y, Kawanami D, Utsunomiya K, Nishimura R. Unraveling the role of inflammation in the pathogenesis of diabetic kidney disease. Int J Mol Sci. 2019;20(14):3393. doi: 10.3390/ijms20143393
Ren N, Wang WF, Zou L, Zhao YL, Miao H, Zhao YY. The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis. Front Pharmacol. 2024;14:1335094.doi: 10.3389/fphar.2023.1335094
Tirichen H, Yaigoub H, Xu W, Wu C, Li R, Li Y. Mitochondrial reactive oxygen species and their contribution in chronic kidney disease progression through oxidative stress. Front Physiol. 2021;12:627837.doi: 10.3389/fphys.2021.627837
Aranda-Rivera AK, Cruz-Gregorio A, Aparicio-Trejo OE, Pedraza-Chaverri J. Mitochondrial redox signaling and oxidative stress in kidney diseases. Biomolecules. 2021;11(8):1144. doi: 10.3390/biom 11081144
Yang Z, Li H, Wu H yan, Zhou Y, Du J xue, Hu Z xue. Omega-3 polyunsaturated fatty acids alleviate hyperuricemic nephropathy by inhibiting renal pyroptosis through GPR120. Biochem Pharmacol. 2024;230:116575.doi: 10.1016/j.bcp.2024.116575
Bozkurt I, Halici Z, Zirh EB, Palabiyik-Yucelik SS. EGCG alleviates Ochratoxin A-induced pyroptosis in rat’s kidney by inhibiting NLRP3/Caspase-1/GSDMD signaling pathway. Food and Chemical Toxicology. 2024;193:115006.doi: 10.1016/j.fct.2024.115006
Liu Y, Lei H, Zhang W, Xing Q, Liu R, Wu S, et al. Pyroptosis in renal inflammation and fibrosis: current knowledge and clinical significance. Cell Death Dis. 2023;14(7):472.doi: 10.1038/s41419-023-05810-9
Li X, Gao L, Li X, Xia J, Pan Y, Bai C. Autophagy, pyroptosis and ferroptosis are rising stars in the pathogenesis of diabetic nephropathy. Diabetes, Metabolic Syndrome and Obesity. 2024;1289–99.doi: 10.2147/DMSO.S438921
Liu J, Chen J, Lv J, Gong Y, Song J. The mechanisms of ferroptosis in the pathogenesis of kidney diseases. J Nephrol. 2024;37(4):865–79.doi: 10.1007/s40620-023-01690-0
Khor BH, Narayanan SS, Sahathevan S, Gafor AHA, Daud ZAM, Khosla P, et al. Efficacy of nutritional interventions on inflammatory markers in haemodialysis patients: A systematic review and limited meta-analysis. Nutrients. 2018;10(4):397.doi: 10.3390/nu10040397
An WS, Kim HJ, Cho KH, Vaziri ND. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. American Journal of Physiology-Renal Physiology. 2009;297(4):F895–903.doi: 10.1152/ajprenal.90708.2008
Muramatsu H, Akimoto N, Yajima K, Hashimoto M, Katakura M. Suppressing Effects of Docosahexaenoic Acid–Containing Diets on Oxidative Stress and Fibrosis in 5/6 Nephrectomized Rats. Kidney360. 2023;4(12):1690–701.doi: 10.34067/KID.0004152023
Kapoor R, Huang YS. Gamma linolenic acid: an antiinflammatory omega-6 fatty acid. Curr Pharm Biotechnol. 2006;7(6):531–4.doi: 10.2174/138920106779116873
Yalçınkaya A, Acar F, Özer Ö, Ozturk HS, Yagmurdur H, Bayazit D. The Effects of EPA, GLA, and Antioxidant-Enriched Enteral Nutrition on Oxidative Stress and Oxygenation in Patients With ARDS: A Prospective, Randomized, Controlled Trial. South Clin Istanb Eurasia. 2025;36(1):16.doi: 10.14744/scie.2025.57805
Rahimi K, Givi ME, Rezaie A, Hekmatmanesh M, Ardakani YS. The protective effects of Gamma-linolenic acid against indomethacin-induced gastric ulcer in rats. British Journal of Nutrition. 2024;131(11):1844–51.doi: 10.1017/S0007114524000268
Rahimi K, Nourishirazi A, Delaviz H, Ghotbeddin Z. Antinociceptive effects of gamma-linolenic acid in the formalin test in the rats. Annals of Medicine and Surgery. 2024;86(5):2677–83.doi: 10.1016/j.amsu.2024.2677
Kim DH, Yoo TH, Lee SH, Kang HY, Nam BY, Kwak SJ, et al. Gamma linolenic acid exerts anti-inflammatory and anti-fibrotic effects in diabetic nephropathy. Yonsei Med J. 2012;53(6):1165.doi: 10.3349/ymj.2012.53.6.1165
İstifli ES, Demir E, Kaplan HM, Ateş KE, Doran F. Alpha-linolenic acid confers protection on mice renal cells against cisplatin-induced nephrotoxicity. Cytotechnology. 2019;71(5):905–14. doi:10.1007/ s10616-019-00327-4
Montecillo-Aguado M, Tirado-Rodriguez B, Huerta-Yepez S. The involvement of polyunsaturated fatty acids in apoptosis mechanisms and their implications in cancer. Int J Mol Sci. 2023;24(14):11691.doi: 10.3390/ijms241411691
Guerrero-Hue M, Rayego-Mateos S, Vázquez-Carballo C, Palomino-Antolín A, García-Caballero C, Opazo-Rios L, et al. Protective role of Nrf2 in renal disease. Antioxidants. 2020;10(1):39.doi: 10.3390/antiox10010039
Colquhoun A. Gamma-linolenic acid alters the composition of mitochondrial membrane subfractions, decreases outer mitochondrial membrane binding of hexokinase and alters carnitine palmitoyltransferase I properties in the Walker 256 rat tumour. Biochimica et Biophysica Acta (BBA)-Molecular and cell biology of lipits. 2002;1583(1):74–84.doi: 10.1016/S1388-1981(02)00046-4
Hosohata K, Jin D, Takai S. Glaucocalyxin A ameliorates hypoxia/reoxygenation-induced injury in human renal proximal tubular epithelial cell line HK-2 cells. Int J Mol Sci. 2021;23(1):446. doi: 10.3390/ijms23010446
Wei Z, Ding H, Li H, Yin D, Cao J. Eicosapentaenoic Acid Modulates TGF-β1/Smad3/ILK Pathway to Attenuate Renal Fibrosis: A Biotechnological Approach. Iran J Biotechnol. 2025;23(2):e4098.doi: 10.30498/ijb.2025.513787.4098
Zeng Z, Yang H, Wang Y, Ren J, Dai Y, Dai C. Omega-3 polyunsaturated fatty acids attenuate fibroblast activation and kidney fibrosis involving MTORC2 signaling suppression. Sci Rep. 2017;7(1):46146. doi: 10.1038/srep46146
Yamamoto T, Takabatake Y, Minami S, Sakai S, Fujimura R, Takahashi A, et al. Eicosapentaenoic acid attenuates renal lipotoxicity by restoring autophagic flux. Autophagy. 2021;17(7):1700–13. doi: 10.1080/15548627.2020.1848052
Diaz M, Retamal MA. Modulation of ion channels and ionic pumps by fatty acids: implications in physiology and pathology. Vol. 9, Frontiers in Physiology. Frontiers Media SA; 2018. p. 1625.doi: 10.3389/fphys.2018.01625
Tallima H, El Ridi R. Arachidonic acid: physiological roles and potential health benefits–a review. J Adv Res. 2018;11:33–41.doi: 10.1016/j.jare.2017.11.003
Chewcharat A, Chewcharat P, Rutirapong A, Papatheodorou S. The effects of omega-3 fatty acids on diabetic nephropathy: A meta-analysis of randomized controlled trials. PLoS One. 2020;15(2):e0228315.doi: 10.1371/journal.pone.0228315
Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med. 2008;233(6):674–88. DOI: 10.3181/0711-MR-311
Ismail TF, Aziz FM. The Protective Effect of Omega-3 Oil against Cadmium Chloride Induced Nephrotoxicity in Rat.doi:10.24086/ cuesj.si.2017.n2a15
Chen Z, Lu Q, Wang J, Cao X, Wang K, Wang Y, et al. The function of omega-3 polyunsaturated fatty acids in response to cadmium exposure. Front Immunol. 2022;13:1023999. doi:10.3389/ fimmu.2022.1023999
Elsafty M, Abdeen A, Aboubakr M. Allicin and Omega-3 fatty acids attenuates acetaminophen mediated renal toxicity and modulates oxidative stress, and cell apoptosis in rats. Naunyn Schmiedebergs Arch Pharmacol. 2024;397(1):317–28.doi:10.1007/s00210-023-02673-1
Bolat M, Bolat İ, Tekin S, Çelebi F. The Effect of Borage Oil (Borago officinalis) on Lead Acetate-Induced Cardiotoxicity. Van Veterinary Journal. 2025;36(3):254–60.doi:10.36483/vanvetj.1774021
Tasset-Cuevas I, Fernández-Bedmar Z, Lozano-Baena MD, Campos-Sánchez J, de Haro-Bailón A, Muñoz-Serrano A, et al. Protective effect of borage seed oil and gamma linolenic acid on DNA: in vivo and in vitro studies. PLoS One. 2013;8(2):e56986. doi: 10.1371/journal.pone.0056986
Abd Alhusen SK, Hasan AF. Evaluating the renoprotective effects of omega-3-6-9 against cisplatin-induced nephrotoxicity in mice. J Med Life. 2023;16(12):1756.doi: 10.3892/jml.2023.1756
Hassan HA, Edrees GM, El-Gamel EM, El-Sayed EA. Proanthocyanidin and fish oil potent activity against cisplatin-induced renal cell cycle arrest and apoptosis in rats. Ren Fail. 2015;37(8):1356–62. doi: 10.3109/0886022X.2015.1066923
Rengachar P, Bhatt AN, Polavarapu S, Veeramani S, Krishnan A, Sadananda M, et al. Gamma-linolenic acid (GLA) protects against ionizing radiation-induced damage: An In vitro and In vivo study. Biomolecules. 2022;12(6):797. doi: 10.3390/biom12060797
