The Effect of Adropin and Spexin Peptides on Cardiac COX and LOX Gene Expressions in Chronic Renal Failure Model

Yıl 2022, , 1013 - 1023, 27.09.2022

Burak Yazgan , Gülsün Memi

https://doi.org/10.37989/gumussagbil.1097666

Öz

In this study, it was aimed to examine the effects of adropin and spexin peptides on cyclooxygenase (COX) and arachidonate lipoxygenase (ALOX) gene expressions in cardiac damage developing in the axis of chronic renal failure. The Chronic Renal Failure (CRF) model in rats was established by gavage administration of adenine hemisulfate solution for 10 days. Peptides were administered intramuscularly for 4 weeks at doses of 35 µg/kg for spexin treatment and 2.1 µg/kg for adropin treatment. Renal functions were measured with an autoanalyzer. COX1, COX2, ALOX12 and ALOX15 mRNA expressions in cardiac tissue were measured by real time PCR after total RNA isolation and cDNA synthesis. There was no significant difference in COX1 and COX2 expressions between the control and CRF groups. While ALOX12 gene expression decreased in the CRF group compared to the control group, on the contrary, ALOX15 increased. Spexin treatment reduced COX2 and ALOX15 levels compared to the CRF group. In addition, adropin treatment increased the expression of COX1 and decreased the amount of COX2 and ALOX15. Similarly, it was observed that adropin + spexin treatment increased the expression of COX1 and decreased COX2 and ALOX15. Our findings indicate that adropin and spexin peptides affect COX and ALOX levels, providing both the regulation of cardiorenal functions and the modulation of inflammatory processes.

Anahtar Kelimeler

Adropin, Arachidonate lipoxygenase, Chronic renal failure, Cyclooxygenase, Spexin

Proje Numarası

Sırasıyla; FMB-BAP 19-0387 ve 2018/118

Adropin ve Speksin Peptitlerinin Kronik Renal Yetmezlik Modelinde Kardiyak COX ve LOX Gen Ekspresyonları Üzerine Etkisi

Öz

Bu çalışmada adropin ve speksin peptitlerinin siklooksijenaz (COX) ve araşidonat lipooksijenaz (ALOX) gen ekspresyonları üzerindeki etkisinin kronik renal yetmezlik ekseninde gelişen kardiyak hasarda incelenmesi amaçlanmıştır. Sıçanlarda Kronik Renal Yetmezlik (KRY) modeli 10 gün boyunca adenin hemisülfat çözeltisinin gavaj yoluyla verilmesiyle oluşturulmuştur. Speksin tedavisi için 35 µg/kg ve adropin tedavisi için 2,1 µg/kg dozlarda peptitler 4 hafta boyunca intramusküler olarak uygulanmıştır. Renal fonksiyonlar otoanalizör ile ölçülmüştür. Kardiyak dokudaki COX1, COX2, ALOX12 ve ALOX15 mRNA ekpsresyonları total RNA izolasyonu ve cDNA sentezi sonrasında real time PCR ile ölçülmüştür. Kontrol ve KRY grubu arasında COX1 ve COX2 ekspresyonlarında anlamlı bir fark gözlenmemiştir. Kontrol grubuna kıyasla KRY grubunda ALOX12 gen ekspresyonu azalırken, tam tersi ALOX15 artmıştır. Speksin tedavisi COX2 ve ALOX15 seviyelerini KRY grubuna kıyasla azaltmıştır. Buna ek olarak, adropin tedavisi COX1 ekspresyonunu arttırırken, COX2 ve ALOX15 miktarını azaltmıştır. Benzer olarak uygulanan adropin+speksin tedavisinin COX1 ekspresyonunu arttırırken, COX2 ve ALOX15’i azalttığı gözlenmiştir. Çalışmamızda elde ettiğimiz bulgular adropin ve speksin peptitlerinin COX ve ALOX seviyelerini etkileyerek hem kardiyorenal fonksiyonların düzenlenmesini hem de inflamatuvar süreçlerin modülasyonunu sağladığını göstermektedir.

Anahtar Kelimeler

Adropin, Araşidonat lipooksijenaz, Kronik renal yetmezlik, Siklooksijenaz, Speksin

Destekleyen Kurum

Amasya Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi ve Trakya Üniversitesi Bilimsel Araştırma Projeleri Koordinatörlüğü

Proje Numarası

Sırasıyla; FMB-BAP 19-0387 ve 2018/118

Kaynakça

• 1. Levin, A, Tonelli, M, Bonventre, J, Coresh, J, Donner, J.A, Fogo, A.B, Fox, C.S, Gansevoort, R.T, Heerspink, H.J.L, Jardine, M, Kasiske, B, Köttgen, A, Kretzler, M, Levey, A.S, Luyckx, V.A, Mehta, R, Moe, O, Obrador, G, Pannu, N, Parikh, C.R, Perkovic, V, Pollock, C, Stenvinkel, P, Tuttle, K.R, Wheeler, D.C. and Eckardt, K.U. (2017). “ISN Global Kidney Health Summit Participants. Global Kidney Health 2017 and Beyond: A Roadmap for Closing Gaps in Care, Research, and Policy”. Lancet, 390 (10105), 1888-1917. https://doi.org/10.1016/S0140-6736(17)30788-2
• 2. Go, A.S, Chertow, G.M, Fan, D, McCulloch, C.E. and Hsu, C.Y. (2004). “Chronic Kidney Disease and The Risks of Death, Cardiovascular Events, and Hospitalization”. New England Journal of Medicine, 351 (13), 1296-1305. https://doi.org/10.1056/nejmoa041031
• 3. Collins, A.J, Foley, R.N, Gilbertson, D.T. and Chen, S.C. (2015). “United States Renal Data System Public Health Surveillance of Chronic Kidney Disease and End-Stage Renal Disease”. Kidney International Supplements, 5 (1), 2-7. https://doi.org/10.1038/kisup.2015.2
• 4. Rahman, S. and Malcoun, A. (2014). “Nonsteroidal Antiinflammatory Drugs, Cyclooxygenase-2, and The Kidneys”. Prim Care, 41 (4), 803-821. https://doi.org/10.1016/j.pop.2014.09.001
• 5. Liaras, K, Fesatidou, M. and Geronikaki, A. (2018). “Thiazoles and Thiazolidinones As COX/LOX Inhibitors”. Molecules, 23 (3), 685. https://doi.org/10.3390/molecules23030685
• 6. Fujihara, C.K, Antunes, G.R, Mattar, A.N.A.L, Andreoli, N, Avancini, D.M, Malheiros, C, Noronha, I.L. and Zatz, R. (2003). “Cyclooxygenase-2 (COX-2) Inhibition Limits Abnormal COX-2 Expression and Progressive Injury in The Remnant Kidney”. Kidney International, 64 (6), 2172-2181. https://doi.org/10.1046/j.1523-1755.2003.00319.x
• 7. Krämer, B.K, Kammerl, M.C. and Kömhoff, M. (2004). “Renal Cyclooxygenase-2 (Cox-2)”. Kidney and Blood Pressure Research, 27 (1), 43-62. https://doi.org/10.1159/000075811
• 8. Parente, L. and Perretti, M. (2003). “Advances in The Pathophysiology of Constitutive and Inducible Cyclooxygenases: Two Enzymes in The Spotlight”. Biochemical Pharmacology, 65 (2), 153-159. https://doi.org/10.1016/S0006-2952(02)01422-3
• 9. Radi, Z.A. (2009). “Pathophysiology of Cyclooxygenase Inhibition in Animal Models”. Toxicologic Pathology, 37 (1), 34-46. https://doi.org/10.1177%2F0192623308329474
• 10. Mitchell, J.A. and Kirkby, N.S. (2019). “Eicosanoids, Prostacyclin and Cyclooxygenase in The Cardiovascular System”. British Journal of Pharmacology, 176 (8), 1038-1050. https://doi.org/10.1111/bph.14167
• 11. Newcomer, M.E. and Brash, A.R. (2015). “The Structural Basis for Specificity in Lipoxygenase Catalysis”. Protein Science, 24 (3), 298-309. https://doi.org/10.1002/pro.2626
• 12. Giménez-Bastida, J.A, González-Sarrías, A, Laparra-Llopis, J.M, Schneider, C. and Espín, J.C. (2021). “Targeting Mammalian 5-Lipoxygenase by Dietary Phenolics As An Anti-Inflammatory Mechanism: A Systematic Review”. International Journal of Molecular Sciences, 22 (15), 7937. https://doi.org/10.3390/ijms22157937
• 13. Michiels, C., Bouaziz, N. and Remacle, J. (2002). “Role of The Endothelium and Blood Stasis in The Appearance of Varicose Veins”. International Angiology, 21 (2), 18-25.
• 14. Kain, V, Ingle, K.A, Kabarowski, J, Barnes, S, Limdi, N.A, Prabhu, S.D. and Halade, G.V. (2018). “Genetic Deletion of 12/15 Lipoxygenase Promotes Effective Resolution of Inflammation Following Myocardial Infarction”. Journal of Molecular and Cellular Cardiology, 118, 70-80. https://doi.org/10.1016/j.yjmcc.2018.03.004
• 15. Wen, Y, Gu, J, Peng, X, Zhang, G. and Nadler, J. (2003). “Overexpression of 12-Lipoxygenase and Cardiac Fibroblast Hypertrophy”. Trends in Cardiovascular Medicine, 13 (4), 129-136. https://doi.org/10.1016/S1050-1738(03)00027-6
• 16. Cicero, A.F, Derosa, G. and Gaddi, A. (2005). “Combined Lipoxygenase/Cyclo-Oxygenase Inhibition in The Elderly: The Example of Licofelone”. Drugs Aging, 22 (5), 393-403. https://doi.org/10.2165/00002512-200522050-00004
• 17. Mirabeau, O, Perlas, E, Severini, C, Audero, E, Gascuel, O, Possenti, R, Birney, E, Rosenthal, N. and Gross, C. (2007). “Identification of Novel Peptide Hormones in The Human Proteome by Hidden Markov Model Screening”. Genome Research, 17 (3), 320-7. http://www.genome.org/cgi/doi/10.1101/gr.5755407
• 18. Lv, S.Y, Zhou, Y.C, Zhang, X.M, Chen, W.D. and Wang, Y.D. (2019). “Emerging Roles of NPQ/Spexin in Physiology and Pathology”. Frontiers in Pharmacology, 10, 457. https://doi.org/10.3389/fphar.2019.00457
• 19. Gu, L, Ma, Y, Gu, M, Zhang, Y, Yan, S, Li, N, Wang, Y, Ding, X, Yin, J, Fan, N. and Peng, Y. (2015). “Spexin Peptide Is Expressed in Human Endocrine and Epithelial Tissues and Reduced After Glucose Load in Type 2 Diabetes”. Peptides, 71, 232-39. https://doi.org/10.1016/j.peptides.2015.07.018
• 20. Kim, D.K, Yun, S, Son, G.H, Hwang, J.I, Park, C.R, Kim, J.I, Kim, K, Vaudry, H. and Seong, J.Y. (2014). “Coevolution of The Spexin/Galanin/Kisspeptin Family: Spexin Activates Galanin Receptor Type II and III”. Endocrinology, 155 (5), 1864-1873. https://doi.org/10.1210/en.2013-2106
• 21. Lv, S.Y, Zhou, Y.C, Zhang, X.M, Chen, W.D. and Wang, Y.D. (2019). “Emerging Roles of NPQ/Spexin in Physiology and Pathology”. Frontiers in Pharmacology, 10, 457. https://doi.org/10.3389/fphar.2019.00457
• 22. Türkel, İ, Memi, G. and Yazgan, B. (2022). “Impact of Spexin on Metabolic Diseases and Inflammation: An Updated Minireview”. Experimental Biology and Medicine, 247 (7), 567-573. https://doi.org/10.1177%2F15353702211072443
• 23. Kumar, K.G, Trevaskis, J.L, Lam, D.D, Sutton, G.M, Koza, R.A, Chouljenko, V.N, Kousoulas, K.G, Rogers, P.M, Kesterson, R.A, Thearle, M, Ferrante, A.W, Mynatt, R.L, Burris, T.P, Dong, J.Z, Halem, H.A, Culler, M.D, Heisler, L.K, Stephens, J.M. and Butler, A.A. (2008). “Identification of Adropin As A Secreted Factor Linking Dietary Macronutrient Intake with Energy Homeostasis and Lipid Metabolism”. Cell Metabolism, 8 (6), 468-81. https://doi.org/10.1016/j.cmet.2008.10.011
• 24. Jasaszwili, M, Billert, M, Strowski, M.Z, Nowak, K.W. and Skrzypski, M. (2020). “Adropin As A Fat-Burning Hormone with Multiple Functions—Review of A Decade of Research”. Molecules, 25 (3), 549. https://doi.org/10.3390/molecules25030549
• 25. Aydin, S. (2014). “Three New Players in Energy Regulation: Preptin, Adropin and Irisin”. Peptides, 56, 94-110. https://doi.org/10.1016/j.peptides.2014.03.021
• 26. Altamimi, T.R, Gao, S, Karwi, Q.G, Fukushima, A, Rawat, S, Wagg, C.S, Zhang, L. and Lopaschuk, G.D. (2019). “Adropin Regulates Cardiac Energy Metabolism and Improves Cardiac Function and Efficiency”. Metabolism, 98, 37-48. https://doi.org/10.1016/j.metabol.2019.06.005
• 27. Lian, W, Gu, X, Qin, Y. and Zheng, X. (2011). “Elevated Plasma Levels of Adropin in Heart Failure Patients”. Internal Medicine, 50 (15), 1523-27. https://doi.org/10.2169/internalmedicine.50.5163
• 28. Topuz, M, Celik, A, Aslantas, T, Demir, A.K, Aydin, S. and Aydin, S. (2013). “Plasma Adropin Levels Predict Endothelial Dysfunction Like Flow-Mediated Dilatation in Patients with Type 2 Diabetes Mellitus”. Journal of Investigative Medicine, 61 (8), 1161-64. http://dx.doi.org/10.2310/JIM.0000000000000003
• 29. Gulen, B, Eken, C, Kucukdagli, O.T, Serinken, M, Kocyigit, A, Kılıc, E. and Uyarel, H. (2016). “Adropin Levels and Target Organ Damage Secondary to High Blood Pressure in The ED”. The American Journal of Emergency Medicine, 34 (11), 2061-64. https://doi.org/10.1016/j.ajem.2016.04.014
• 30. Hu, W. and Chen, L. (2016). “Association of Serum Adropin Concentrations with Diabetic Nephropathy”. Mediators of Inflammation, 2016, 6038261. https://doi.org/10.1155/2016/6038261
• 31. Maciorkowska, M, Musiałowska, D. and Małyszko, J. (2019). “Adropin and Irisin in Arterial Hypertension, Diabetes Mellitus and Chronic Kidney Disease”. Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University, 28 (11), 1571-1575. https://doi.org/10.17219/acem/104551
• 32. Akcilar, R, Kocak, F.E, Simsek, H, Akcilar, A, Bayat, Z, Ece, E. and Kokdasgil, H. (2016). “Antidiabetic and Hypolipidemic Effects of Adropinin Streoptozotocin-Induced Type 2 Diabetic Rats”. Bratıslava Medıcal Journal- Bratislavske lekarske listy, 117 (2), 100-105. https://doi.org/10.3390/diseases9020043
• 33. Deferrari, G, Cipriani, A. and La Porta, E. (2021). “Renal Dysfunction in Cardiovascular Diseases and Its Consequences”. Journal of Nephrology, 34 (1), 137-153. https://doi.org/10.1007/s40620-020-00842-w
• 34. Yazgan, B, Avcı, F, Memi, G. and Tastekin, E. (2021). “Inflammatory Response and Matrix Metalloproteinases in Chronic Kidney Failure: Modulation by Adropin and Spexin”. Experimental Biology and Medicine, 246 (17), 1917-1927. https://doi.org/10.1177/15353702211012417
• 35. Memi, G. and Yazgan, B. (2021). “Adropin and Spexin Hormones Regulate The Systemic Inflammation in Adenine-Induced Chronic Kidney Failure in Rat”. Chinese Journal of Physiology, 64 (4), 194. https://doi.org/10.4103/cjp.cjp_13_21
• 36. Wan, Q, Kong, D, Liu, Q, Guo, S, Wang, C, Zhao, Y, Ke, Z.J. and Yu, Y. (2021). “Congestive Heart Failure in COX2 Deficient Rats”. Science China Life Sciences, 64 (7), 1068-1076. https://doi.org/10.1007/s11427-020-1792-5
• 37. Zheng, Z, Li, Y, Jin, G, Huang, T, Zou, M. and Duan, S. (2020). “The Biological Role of Arachidonic Acid 12-Lipoxygenase (ALOX12) in Various Human Diseases”. Biomedicine & Pharmacotherapy, 129, 110354. https://doi.org/10.1016/j.biopha.2020.110354
• 38. Gertow, K, Nobili, E, Folkersen, L, Newman, J.W, Pedersen, T.L, Ekstrand, J, Swedenborg, J, Kühn, H, Wheelock, C.E, Hansson, G.K, Hedin, U, Haeggström, J.Z. and Gabrielsen, A. (2011). “12-and 15-Lipoxygenases in Human Carotid Atherosclerotic Lesions: Associations with Cerebrovascular Symptoms”. Atherosclerosis, 215 (2), 411-416. https://doi.org/10.1016/j.atherosclerosis.2011.01.015
• 39. Lundqvist, A, Sandstedt, M, Sandstedt, J, Wickelgren, R, Hansson, G.I, Jeppsson, A. and Hultén, L.M. (2016). “The Arachidonate 15-Lipoxygenase Enzyme Product 15-HETE Is Present in Heart Tissue from Patients with Ischemic Heart Disease and Enhances Clot Formation”. Plos One, 11 (8), e0161629. https://doi.org/10.1371/journal.pone.0161629
• 40. Askin, L, Askin, H.S, Tanriverdi, O. and Hosoglu, Y. (2022). “Serum Adropin: Pathogenesis and Clinical Research in Cardiovascular Disease”. Erciyes Medical Journal, 44 (1), 8-12. https://doi.org/10.14744/etd.2021.23571