Document Type : Research Paper I Open Access I Released under (CC BY-NC) license

Authors

1 Department of Exercise Physiology, Tabriz branch, Islamic Azad University, Tabriz, Iran

2 : Assistant Prof., Department of Exercise Physiology, Tabriz branch, Islamic Azad University, Tabriz, Iran

Abstract

Aim: Was to investigate the effects of eight weeks aerobic training and curcumin supplementation on some mitophagy indices induced by ischemia/reperfusion of male rats. Methods: Fifty eight (age: 12 weeks, weight: 315.23 ± 28.57 gr) male rats were randomized into five groups including on Healthy control, Ischemic cotrol, Curcumin, Training, Training+Curcumin(Concomitant). Aerobic training program were conducted for eight weeks (5 d/w) starting with running at a speed of 10 m/min, 5% incline for 10 min per day. The running speed and time were gradually increased up to 15-20 m/min per day. In the last two sessions, the intensity of aerobic training reached 25 m/min for 30 min per day with 2 min recovery period at 10 m/min. curcumin (200 mg/bw.day) were consumed through oral gavage for six weeks. The gene expression levels of miR-1 and miR-133 were evaluated using Real-Time PCR method and the data were analyzed using one-way analysis of variance and Tukey post hoc test at the significance level of p <0.05. Results: In all four intervention groups, including ischemia control, exercise, curcumin and combination, the expression of HIF-1α and BNIP3 in renal tissue increased significantly (p=0.001 in all groups) compared to the control group. However, the expression of HIF-1α and BNIP3 genes in renal tissue after exercise caused a significant decrease and increase (p=0.007 and p=0.01, respectively) compared to the healthy control and ischemic control groups. Also, curcumin and Concomitant were associated with an increase in HIF-1α and BNIP3 gene expression in renal tissue

Keywords

Main Subjects

  1. Bellomo R, Kellum JA, Ronco C. Acute kidney injury. The Lancet. 2012;380(9843):756-66.
  2. Sancho-Martínez SM, López-Novoa JM, López-Hernández FJ. Pathophysiological role of different tubular epithelial cell death modes in acute kidney injury. Clinical kidney journal. 2015;8(5):548-59.
  3. Duann P, Lianos EA, Ma J, Lin P-H. Autophagy, innate immunity and tissue repair in acute kidney injury. International journal of molecular sciences. 2016;17(5):662.
  4. Zhang Z, Haimovich B, Kwon YS, Lu T, Fyfe-Kirschner B, Olweny EO. Unilateral partial nephrectomy with warm ischemia results in acute hypoxia inducible factor 1-alpha (HIF-1α) and Toll-like receptor 4 (TLR4) overexpression in a porcine model. PLoS One. 2016;11(5):e0154708.
  5. Pastor-Soler NM, Sutton TA, Mang HE, Kinlough CL, Gendler SJ, Madsen CS, et al. Muc1 is protective during kidney ischemia-reperfusion injury. American Journal of Physiology-Renal Physiology. 2015;308(12):F1452-F62.
  6. Fähling M, Mathia S, Paliege A, Koesters R, Mrowka R, Peters H, et al. Tubular von Hippel-Lindau knockout protects against rhabdomyolysis-induced AKI. Journal of the American Society of Nephrology. 2013;24(11):1806-19.
  7. Conde E, Alegre L, Blanco-Sanchez I, Saenz-Morales D, Aguado-Fraile E, Ponte B, et al. Hypoxia inducible factor 1-alpha (HIF-1 alpha) is induced during reperfusion after renal ischemia and is critical for proximal tubule cell survival. PloS one. 2012;7(3):e33258.
  8. Zou Y-F, Liao W-T, Fu Z-J, Zhao Q, Chen Y-X, Zhang W. MicroRNA-30c-5p ameliorates hypoxia-reoxygenation-induced tubular epithelial cell injury via HIF1α stabilization by targeting SOCS3. Oncotarget. 2017;8(54):92801.
  9. Kaushal GP, Shah SV. Autophagy in acute kidney injury. Kidney international. 2016;89(4):779-91.
  10. Bernhardt WM, Câmpean V, Kany S, Jürgensen J-S, Weidemann A, Warnecke C, et al. Preconditional activation of hypoxia-inducible factors ameliorates ischemic acute renal failure. Journal of the American Society of Nephrology. 2006;17(7):1970-8.
  11. Zhang Q, Bian ZX, Song Y, Wang X, Zhang H, Ren Q, et al. Regulation of mitophagy through HIF‐1α/miR‐140‐5p/PARKIN axis in acute kidney injury. Environmental Toxicology. 2022;37(7):1759-67.
  12. Tang C, Han H, Liu Z, Liu Y, Yin L, Cai J, et al. Activation of BNIP3-mediated mitophagy protects against renal ischemia–reperfusion injury. Cell death & disease. 2019;10(9):1-15.
  13. Li X, Chen W, Feng J, Zhao B. The effects of HIF-1α overexpression on renal injury, immune disorders and mitochondrial apoptotic pathways in renal ischemia/reperfusion rats. Translational Andrology and Urology. 2020;9(5):2157.
  14. Tang C, Han H, Liu Z, Liu Y, Yin L, Cai J, et al. Activation of BNIP3-mediated mitophagy protects against renal ischemia–reperfusion injury. Cell death & disease. 2019;10(9):677.
  15. Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annual Review of Pathology: Mechanisms of Disease. 2014;9:47-71.
  16. Knudsen AR, Kannerup A-S, Dich R, Funch-Jensen P, Grønbæk H, Kruhøffer M, et al. Ischemic pre-and postconditioning has pronounced effects on gene expression profiles in the rat liver after ischemia/reperfusion. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2012;303(4):G482-G9.

                                                                                                            

  1. Chourasia AH, Tracy K, Frankenberger C, Boland ML, Sharifi MN, Drake LE, et al. Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO reports. 2015;16(9):1145-63.
  2. Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, et al. Effects of melatonin on fatty liver disease: The role of NR 4A1/DNA‐PK cs/p53 pathway, mitochondrial fission, and mitophagy. Journal of Pineal Research. 2018;64(1):e12450.
  3. Liu L, Sakakibara K, Chen Q, Okamoto K. Receptor-mediated mitophagy in yeast and mammalian systems. Cell research. 2014;24(7):787-95.
  4. O’Sullivan TE, Johnson LR, Kang HH, Sun JC. BNIP3-and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity. 2015;43(2):331-42.
  5. Burton TR, Gibson SB. The role of Bcl-2 family member BNIP3 in cell death and disease: NIPping at the heels of cell death. Cell Death & Differentiation. 2009;16(4):515-23.
  6. Kale J, Osterlund EJ, Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death & Differentiation. 2018;25(1):65-80.
  7. Zhang T, Xue L, Li L, Tang C, Wan Z, Wang R, et al. BNIP3 protein suppresses PINK1 kinase proteolytic cleavage to promote mitophagy. Journal of biological chemistry. 2016;291(41):21616-29.
  8. Glick D, Zhang W, Beaton M, Marsboom G, Gruber M, Simon MC, et al. BNip3 regulates mitochondrial function and lipid metabolism in the liver. Molecular and cellular biology. 2012;32(13):2570-84.
  9. Ishihara M, Urushido M, Hamada K, Matsumoto T, Shimamura Y, Ogata K, et al. Sestrin-2 and BNIP3 regulate autophagy and mitophagy in renal tubular cells in acute kidney injury. American Journal of Physiology-Renal Physiology. 2013;305(4):F495-F509.
  10. Esatbeyoglu T, Huebbe P, Ernst IM, Chin D, Wagner AE, Rimbach G. Curcumin—from molecule to biological function. Angewandte Chemie International Edition. 2012;51(22):5308-32.
  11. Yeh C-H, Chen T-P, Wu Y-C, Lin Y-M, Lin PJ. Inhibition of NFκB activation with curcumin attenuates plasma inflammatory cytokines surge and cardiomyocytic apoptosis following cardiac ischemia/reperfusion1. Journal of Surgical Research. 2005;125(1):109-16.
  12. Molina-Jijón E, Tapia E, Zazueta C, El Hafidi M, Zatarain-Barrón ZL, Hernández-Pando R, et al. Curcumin prevents Cr (VI)-induced renal oxidant damage by a mitochondrial pathway. Free Radical Biology and Medicine. 2011;51(8):1543-57.
  13. Yang L, Chen X, Bi Z, Liao J, Zhao W, Huang W. Curcumin attenuates renal ischemia reperfusion injury via JNK pathway with the involvement of p300/CBP-mediated histone acetylation. The Korean journal of physiology & pharmacology: official journal of the Korean Physiological Society and the Korean Society of Pharmacology. 2021;25(5):413-23.
  14. Zhu P, Yang M, He H, Kuang Z, Liang M, Lin A, et al. Curcumin attenuates hypoxia/reoxygenation‑induced cardiomyocyte injury by downregulating Notch signaling. Molecular Medicine Reports. 2019;20(2):1541-50.
  15. Shen S-Q, Zhang Y, Xiang J-J, Xiong C-L. Protective effect of curcumin against liver warm ischemia/reperfusion injury in rat model is associated with regulation of heat shock protein and antioxidant enzymes. World journal of gastroenterology: WJG. 2007;13(13):1953.
  16. Yucel AF, Kanter M, Pergel A, Erboga M, Guzel A. The role of curcumin on intestinal oxidative stress, cell proliferation and apoptosis after ischemia/reperfusion injury in rats. Journal of Molecular Histology. 2011;42(6):579-87.
  17. Liu F, Ni W, Zhang J, Wang G, Li F, Ren W. Administration of curcumin protects kidney tubules against renal ischemia-reperfusion injury (RIRI) by modulating nitric oxide (NO) signaling pathway. Cellular Physiology and Biochemistry. 2017;44(1):401-11.
  18. Kim YS, Kwon JS, Cho YK, Jeong MH, Cho JG, Park JC, et al. Curcumin reduces the cardiac ischemia–reperfusion injury: involvement of the toll-like receptor 2 in cardiomyocytes. The Journal of nutritional biochemistry. 2012;23(11):1514-23.
  19. Han J, Pan X-Y, Xu Y, Xiao Y, An Y, Tie L, et al. Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage. Autophagy. 2012;8(5):812-25.
  20. Formigari GP, Dátilo MN, Vareda B, Bonfante ILP, Cavaglieri CR, Lopes de Faria JM, et al. Renal protection induced by physical exercise may be mediated by the irisin/AMPK axis in diabetic nephropathy. Scientific Reports. 2022;12(1):1-11.
  21. Wilkinson TJ, Shur NF, Smith AC. “Exercise as medicine” in chronic kidney disease. Scandinavian journal of medicine & science in sports. 2016;26(8):985-8.
  22. de Lima WV, Visona I, Schor N, Almeida WS. Preconditioning by aerobic exercise reduces acute ischemic renal injury in rats. Physiological reports. 2019;7(14):e14176.
  23. Elsaid FH, Khalil AA, Ibrahim EM, Mansour A, Hussein AM. Effects of exercise and stevia on renal ischemia/reperfusion injury in rats. Acta scientiarum polonorum Technologia alimentaria. 2019;18(3).
  24. Yan Z, Lira VA, Greene NP. Exercise training-induced regulation of mitochondrial quality. Exercise and sport sciences reviews. 2012;40(3):159-64.
  25. Ding H, Jiang N, Liu H, Liu X, Liu D, Zhao F, et al. Response of mitochondrial fusion and fission protein gene expression to exercise in rat skeletal muscle. Biochimica et Biophysica Acta (BBA)-General Subjects. 2010;1800(3):250-6.
  26. Leermakers PA, Gosker HR. Skeletal muscle mitophagy in chronic disease: implications for muscle oxidative capacity? Current opinion in clinical nutrition and metabolic care. 2016;19(6):427-33.
  27. Shang H, Xia Z, Bai S, Zhang H, Gu B, Wang R. Downhill Running Acutely Elicits Mitophagy in Rat Soleus Muscle. Medicine and Science in Sports and Exercise. 2019;51(7):1396-403.
  28. Wang Q, Xu J, Li X, Liu Z, Han Y, Xu X, et al. Sirt3 modulate renal ischemia‐reperfusion injury through enhancing mitochondrial fusion and activating the ERK‐OPA1 signaling pathway. Journal of Cellular Physiology. 2019;234(12):23495-506.
  29. Fu Z-J, Wang Z-Y, Xu L, Chen X-H, Li X-X, Liao W-T, et al. HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury. Redox biology. 2020;36:101671.
  30. Linkermann A, Chen G, Dong G, Kunzendorf U, Krautwald S, Dong Z. Regulated cell death in AKI. Journal of the American Society of Nephrology. 2014;25(12):2689-701.
  31. Haase VH. Mechanisms of hypoxia responses in renal tissue. Journal of the american society of nephrology. 2013;24(4):537-41.
  32. Kroshian VM, Sheridan AM, Lieberthal W. Functional and cytoskeletal changes induced by sublethal injury in proximal tubular epithelial cells. American Journal of Physiology-Renal Physiology. 1994;266(1):F21-F30.
  33. Osada T, Katsumura T, Hamaoka T, Inoue S, Esaki K, Sakamoto A, et al. Reduced blood flow in abdominal viscera measured by Doppler ultrasound during one-legged knee extension. Journal of Applied Physiology. 1999;86(2):709-19.
  34. Badkoubeh-Hezaveh M, Abedi B, Rahmati-Ahmadabad S. The Effect of Regular Aerobic Exercise Training and Pumpkin Seed Extract on the Heart and Aorta Apoptosis Biomarkers in Arsenic-Intoxicated Rats. Gene, Cell and Tissue. 2021;8(2).
  35. Tang C, Lei H, Zhang J, Liu M, Jin J, Luo H, et al. Montelukast inhibits hypoxia inducible factor-1α translation in prostate cancer cells. Cancer Biology & Therapy. 2018;19(8):715-21.
  36. Rosenberger C, Rosen S, Shina A, Frei U, Eckardt K-U, Flippin LA, et al. Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney. Nephrology Dialysis Transplantation. 2008;23(11):3472-8.
  37. Matsumoto M, Makino Y, Tanaka T, Tanaka H, Ishizaka N, Noiri E, et al. Induction of renoprotective gene expression by cobalt ameliorates ischemic injury of the kidney in rats. Journal of the American Society of Nephrology. 2003;14(7):1825-32.
  38. Sutton TA, Wilkinson J, Mang HE, Knipe NL, Plotkin Z, Hosein M, et al. p53 regulates renal expression of HIF-1α and pVHL under physiological conditions and after ischemia-reperfusion injury. American Journal of Physiology-Renal Physiology. 2008;295(6):F1666-F77.
  39. Von Hoermann C, Ruther J, Reibe S, Madea B, Ayasse M. The importance of carcass volatiles as attractants for the hide beetle Dermestes maculatus (De Geer). Forensic Science International. 2011;212(1-3):173-9.
  40. Wu X, Li X, Liu Y, Yuan N, Li C, Kang Z, et al. Hydrogen exerts neuroprotective effects on OGD/R damaged neurons in rat hippocampal by protecting mitochondrial function via regulating mitophagy mediated by PINK1/Parkin signaling pathway. Brain Research. 2018;1698:89-98.
  41. Plotnikov E, Kazachenko A, Vyssokikh MY, Vasileva A, Tcvirkun D, Isaev N, et al. The role of mitochondria in oxidative and nitrosative stress during ischemia/reperfusion in the rat kidney. Kidney international. 2007;72(12):1493-502.
  42. Molitoris BA. Actin cytoskeleton in ischemic acute renal failure. Kidney international. 2004;66(2):871-83.
  43. Schrier RW, Wang W, Poole B, Mitra A. Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. The Journal of clinical investigation. 2004;114(1):5-14.
  44. Mazure NM, Pouyssegur J. Hypoxia-induced autophagy: cell death or cell survival? Current opinion in cell biology. 2010;22(2):177-80.

Wu Z, Zhang W, Kang YJ. Copper affects the binding of HIF-1α to the critical motifs of its target genes. Metallomics. 2019;11(2):429-38.

  1. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. Journal of Biological Chemistry. 2008;283(16):10892-903.
  2. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological reviews. 2014;94(3):909-50.
  3. Chourasia AH, Macleod KF. Tumor suppressor functions of BNIP3 and mitophagy. Autophagy. 2015;11(10):1937-8.
  4. Sathiyaseelan P, Rothe K, Yang KC, Xu J, Chow NS, Bortnik S, et al. Diverse mechanisms of autophagy dysregulation and their therapeutic implications: does the shoe fit? Autophagy. 2019;15(2):368-71.
  5. Sylviana N, Helja N, Qolbi HH, Goenawan H, Lesmana R, Syamsunarno MRA, et al. Effect of swimming exercise to cardiac PGC-1 α and HIF-1 α gene expression in mice. Asian Journal of Sports Medicine. 2018;9(4).
  6. Lindholm ME, Fischer H, Poellinger L, Johnson RS, Gustafsson T, Sundberg CJ, et al. Negative regulation of HIF in skeletal muscle of elite endurance athletes: a tentative mechanism promoting oxidative metabolism. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2014;307(3):R248-R55.
  7. Lindholm ME, Rundqvist H. Skeletal muscle hypoxia‐inducible factor‐1 and exercise. Experimental physiology. 2016;101(1):28-32.
  8. Lundby C, Gassmann M, Pilegaard H. Regular endurance training reduces the exercise induced HIF-1α and HIF-2α mRNA expression in human skeletal muscle in normoxic conditions. European journal of applied physiology. 2006;96:363-9.
  9. Radak Z, Bori Z, Koltai E, Fatouros IG, Jamurtas AZ, Douroudos II, et al. Age-dependent changes in 8-oxoguanine-DNA glycosylase activity are modulated by adaptive responses to physical exercise in human skeletal muscle. Free Radical Biology and Medicine. 2011;51(2):417-23.
  10. Ju J-s, Jeon S-i, Park J-y, Lee J-y, Lee S-c, Cho K-j, et al. Autophagy plays a role in skeletal muscle mitochondrial biogenesis in an endurance exercise-trained condition. The Journal of Physiological Sciences. 2016;66:417-30.
  11. Tam B, Pei X, Yu A, Sin T, Leung K, Au K, et al. Autophagic adaptation is associated with exercise‐induced fibre‐type shifting in skeletal muscle. Acta physiologica. 2015;214(2):221-36.
  12. Lira VA, Okutsu M, Zhang M, Greene NP, Laker RC, Breen DS, et al. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. The FASEB Journal. 2013;27(10):4184.
  13. Motterlini R, Foresti R, Bassi R, Green CJ. Curcumin, an antioxidant and anti-inflammatory agent, induces heme oxygenase-1 and protects endothelial cells against oxidative stress. Free Radical Biology and Medicine. 2000;28(8):1303-12.
  14. Huang Z, Ye B, Dai Z, Wu X, Lu Z, Shan P, et al. Curcumin inhibits autophagy and apoptosis in hypoxia/reoxygenation-induced myocytes. Molecular Medicine Reports. 2015;11(6):4678-84.
  15. Kubli DA, Gustafsson ÅB. Mitochondria and mitophagy: the yin and yang of cell death control. Circulation research. 2012;111(9):1208-21.

77. Lin Q, Li S, Jiang N, Jin H, Shao X, Zhu X, et al. Inhibiting NLRP3 inflammasome attenuates apoptosis in contrast-induced acute kidney injury through the upregulation of HIF1A and BNIP3-mediated mitophagy. Autophagy. 2021;17(10):2975-90