研究生: |
高浩瀚 Kao, Hao-Han |
---|---|
論文名稱: |
有氧運動訓練調控能量代謝路徑對糖尿病db/db小鼠腎功能之影響 Effects of aerobic exercise training on regulation of renal energy metabolism by activating AMPK-SIRT1 pathway in diabetic db/db mice |
指導教授: |
劉宏文
Liu, Hung-Wen |
學位類別: |
碩士 Master |
系所名稱: |
體育學系 Department of Physical Education |
論文出版年: | 2019 |
畢業學年度: | 107 |
語文別: | 中文 |
論文頁數: | 45 |
中文關鍵詞: | 腎病變 、SIRT1 、AMPKα 、PGC1-α 、發炎路徑 |
英文關鍵詞: | Diabetic Nephropathy, SIRT1, AMPKα, PGC1-α, Inflammatory pathway |
DOI URL: | http://doi.org/10.6345/NTNU201900716 |
論文種類: | 學術論文 |
相關次數: | 點閱:145 下載:49 |
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Sirtuin 1(SIRT1)、AMP-activated protein kinase (AMPK)及peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1-α)為細胞內調節能量代謝的關鍵樞紐,AMPKα/SIRT1/PGC1α路經的受損伴隨粒線體失能是導致糖尿病腎臟病的機轉之一。長期規律有氧運動可以改善早期糖尿病腎臟病變,避免病症繼續惡化。然而,運動訓練經由AMPKα/SIRT1/PGC1α路徑改善糖尿病腎病變的機制,目前仍尚未釐清。本研究假設為有氧運動訓練能上調腎臟中代謝路徑以及同時抑制發炎路徑的活化,達到改善早期糖尿病腎病變的效果。方法:本研究使用糖尿病動物模式,5週齡 BKS.CgDock7m +/+ Leprdb/J(db/db)小鼠購至國家實驗動物中心,實驗動物在適應一周後,隨機分配控制組(n=8)及運動組(n=8)。運動處方:跑步速度為5.2m/min,每天運動1小時,每週訓練 5 天,共進行 8 週。運動訓練結束後將小鼠犧牲,以PAS染色法觀察腎臟組織型態,西方墨點法(Western blot analyses)分析能量代謝(AMPKα/SIRT1/PGC1-α)及發炎路徑(IκB-α/NF-κB)。結果:八週有氧運動訓練後可以改善db/db小鼠腎絲球基質膜擴張,並增加 SIRT1蛋白表現及AMPKα活性,同時抑制NF-κB磷酸化。IκB-α、PGC1-α在運動組及控制組間無顯差異。結論:本研究證實有氧運動訓練是透過活化能量代謝路徑和抑制發炎路徑來延緩糖尿病腎病變惡化。
The AMPK-SIRT1-PGC-1α axis has a crucial role in regulating the energy metabolism and mitochondrial function. Downregulation of AMPK/SIRT1/PGC1α pathway is the mechanism leading to diabetic nephropathy. The purpose of this study was to determine whether exercise training upregulates the energy metabolism pathway and inhibits inflammatory pathway, thereby preventing the early stages of diabetic nephropathy. Male diabetic(db/db)mice were used in the present study. At the age of 5 weeks, db/db mice were divided into two groups: db/db mice (n =8) with exercise training for 8 weeks (db/db + Ex) and db/db (n = 8) remained sedentary throughout the study. Aerobic exercise training (5.2 m/min, 1 h/day, and 5 days/week for a total of 8 weeks) was started from 5-week-old. The results showed that decreased the glomerular matrix expansion score, increased SIRT1 protein expression and AMPKα activity, and decreased NF-κB phosphorylation were observed in db/db + Ex compared with db/db mice. There were no significant changes in IκB-α and PGC1-α. Therefore, the present study confirms that aerobic exercise training alleviates the progression of diabetic nephropathy by activating AMPK-SIRT1 pathway and inhibiting NF-κB activity.
一、中文部分
黃蘭菁、李貫廷、李育霖、楊偉勛、黃國晉(2013)。2013年美國糖尿病學會臨床治療指引學會臨床治療指引摘要。台北市醫師公會會刊,57(3),23-31
蔡東華(2017)。糖尿病腎病變。中華民國糖尿病衛教學會13(1)。21-24
衛福部衛福部(2016)。https://www.hpa.gov.tw/Pages/List.aspx?nodeid=359
李文欽、黃忠餘、張舜智、許君碩、蕭匡智、巫文平、李智威、田志宏 (2013)。腎絲球腎炎的致病機轉與治療原則。腎臟與透析25(1),1-6。
莊武龍(2015)。美國糖尿病學會(ADA)2015年的治療指引更新
國家實驗研究院. (2017).「BKS.Cg-Dock7m +/+ Leprdb/(J db/db)糖尿病小鼠」. Retrieved from http://webserver.nlac.org.tw/n2/n2-2-1-20.asp
二、外文部分
American Diabetes Association. (2013). Standards of medical care in diabetes—2013. Diabetes care, 36(Supplement 1), S11-S66.
Basu, R. K., Hubchak, S., Hayashida, T., Runyan, C. E., Schumacker, P. T., & Schnaper, H. W. (2011). Interdependence of HIF-1alpha and TGF-beta/Smad3 signaling in normoxic and hypoxic renal epithelial cell collagen expression. Am J Physiol Renal Physiol, 300(4), F898-905. doi:10.1152/ajprenal.00335.2010
Breyer, M. D., Bottinger, E., Brosius, F. C., 3rd, Coffman, T. M., Harris, R. C., Heilig, C. W., . . . Amdcc. (2005). Mouse models of diabetic nephropathy. J Am Soc Nephrol, 16(1), 27-45. doi:10.1681/ASN.2004080648
Canto, C., Jiang, L. Q., Deshmukh, A. S., Mataki, C., Coste, A., Lagouge, M., . . . Auwerx, J. (2010). Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab, 11(3), 213-219. doi:10.1016/j.cmet.2010.02.006
Catherwood, M. A., Powell, L. A., Anderson, P., McMaster, D., Sharpe, P. C., & Trimble, E. R. (2002). Glucose-induced oxidative stress in mesangial cells. Kidney Int, 61(2), 599-608. doi:10.1046/j.1523-1755.2002.00168.x
Chacko, B. K., Reily, C., Srivastava, A., Johnson, M. S., Ye, Y., Ulasova, E., . . . Kalyanaraman, B. (2010). Prevention of diabetic nephropathy in Ins2+/− AkitaJ mice by the mitochondria-targeted therapy MitoQ. Biochemical Journal, 432(1), 9-19.
Chacko, B. K., Reily, C., Srivastava, A., Johnson, M. S., Ye, Y., Ulasova, E., . . . Darley-Usmar, V. (2010). Prevention of diabetic nephropathy in Ins2(+/)(-)(AkitaJ) mice by the mitochondria-targeted therapy MitoQ. Biochem J, 432(1), 9-19. doi:10.1042/BJ20100308
Chung, S. S. M. (2003). Contribution of Polyol Pathway to Diabetes-Induced Oxidative Stress. Journal of the American Society of Nephrology, 14(90003), 233S-236. doi:10.1097/01.asn.0000077408.15865.06
Coimbra, T. M., Janssen, U., Grone, H. J., Ostendorf, T., Kunter, U., Schmidt, H., . . . Floege, J. (2000). Early events leading to renal injury in obese Zucker (fatty) rats with type II diabetes. Kidney Int, 57(1), 167-182. doi:10.1046/j.1523-1755.2000.00836.x
Colberg, S. R., Sigal, R. J., Fernhall, B., Regensteiner, J. G., Blissmer, B. J., Rubin, R. R., . . . American Diabetes, A. (2010). Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. Diabetes Care, 33(12), e147-167. doi:10.2337/dc10-9990
Collins, A. J., Foley, R. N., Gilbertson, D. T., & Chen, S. C. (2015). United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl (2011), 5(1), 2-7. doi:10.1038/kisup.2015.2
Decleves, A. E., Zolkipli, Z., Satriano, J., Wang, L., Nakayama, T., Rogac, M., . . . Sharma, K. (2014). Regulation of lipid accumulation by AMP-activated kinase [corrected] in high fat diet-induced kidney injury. Kidney Int, 85(3), 611-623. doi:10.1038/ki.2013.462
Dong, J., Zhang, X., Zhang, L., Bian, H. X., Xu, N., Bao, B., & Liu, J. (2014). Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKalpha1/SIRT1. J Lipid Res, 55(3), 363-374. doi:10.1194/jlr.M038786
Ghosh, S., Golbidi, S., Werner, I., Verchere, B. C., & Laher, I. (2010). Selecting exercise regimens and strains to modify obesity and diabetes in rodents: an overview. Clin Sci (Lond), 119(2), 57-74. doi:10.1042/CS20090389
Ghosh, S., Khazaei, M., Moien-Afshari, F., Ang, L. S., Granville, D. J., Verchere, C. B., . . . Laher, I. (2009). Moderate exercise attenuates caspase-3 activity, oxidative stress, and inhibits progression of diabetic renal disease in db/db mice. Am J Physiol Renal Physiol, 296(4), F700-708. doi:10.1152/ajprenal.90548.2008
Goldin, A., Beckman, J. A., Schmidt, A. M., & Creager, M. A. (2006). Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation, 114(6), 597-605.
Gutkowska, J., Broderick, T. L., Bogdan, D., Wang, D., Lavoie, J. M., & Jankowski, M. (2009). Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy. J Physiol, 587(Pt 19), 4725-4736. doi:10.1113/jphysiol.2009.176461
Hallan, S., & Sharma, K. (2016). The Role of Mitochondria in Diabetic Kidney Disease. Curr Diab Rep, 16(7), 61. doi:10.1007/s11892-016-0748-0
Holmes, B. F., Kurth-Kraczek, E., & Winder, W. (1999). Chronic activation of 5′-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. Journal of applied physiology, 87(5), 1990-1995.
Hong, Y. A., Lim, J. H., Kim, M. Y., Kim, T. W., Kim, Y., Yang, K. S., . . . Park, C. W. (2014). Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1alpha in db/db mice. PLoS One, 9(5), e96147. doi:10.1371/journal.pone.0096147
Inoguchi, T., Sonta, T., Tsubouchi, H., Etoh, T., Kakimoto, M., Sonoda, N., . . . Sumimoto, H. (2003). Protein kinase C–dependent increase in reactive oxygen species (ROS) production in vascular tissues of diabetes: role of vascular NAD (P) H oxidase. Journal of the American Society of Nephrology, 14(suppl 3), S227-S232.
Ishikawa, Y., Gohda, T., Tanimoto, M., Omote, K., Furukawa, M., Yamaguchi, S., . . . Tomino, Y. (2012). Effect of exercise on kidney function, oxidative stress, and inflammation in type 2 diabetic KK-A(y) mice. Exp Diabetes Res, 2012, 702948. doi:10.1155/2012/702948
Isono, M., Chen, S., Hong, S. W., Iglesias-de la Cruz, M. C., & Ziyadeh, F. N. (2002). Smad pathway is activated in the diabetic mouse kidney and Smad3 mediates TGF-β-induced fibronectin in mesangial cells. Biochemical and biophysical research communications, 296(5), 1356-1365.
Ito, D., Cao, P., Kakihana, T., Sato, E., Suda, C., Muroya, Y., . . . Kiyomoto, H. (2015). Chronic Running Exercise Alleviates Early Progression of Nephropathy with Upregulation of Nitric Oxide Synthases and Suppression of Glycation in Zucker Diabetic Rats. PLoS One, 10(9), e0138037. doi:10.1371/journal.pone.0138037
Kim, M., Lim, J., Youn, H., Hong, Y., Yang, K., Park, H., . . . Choi, B. (2013). Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK–SIRT1–PGC1α axis in db/db mice. Diabetologia, 56(1), 204-217.
Kitada, M., Kume, S., Imaizumi, N., & Koya, D. (2011). Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes, 60(2), 634-643.
Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., & Nathan, D. M. (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England journal of medicine, 346(6), 393-403.
Kume, S., Uzu, T., Horiike, K., Chin-Kanasaki, M., Isshiki, K., Araki, S., . . . Koya, D. (2010). Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J Clin Invest, 120(4), 1043-1055. doi:10.1172/JCI41376
Le Bricon, T., Thervet, E., Froissart, M., Benlakehal, M., Bousquet, B., Legendre, C., & Erlich, D. (2000). Plasma cystatin C is superior to 24-h creatinine clearance and plasma creatinine for estimation of glomerular filtration rate 3 months after kidney transplantation. Clinical Chemistry, 46(8), 1206-1207.
LeBrasseur, N. K., Kelly, M., Tsao, T. S., Farmer, S. R., Saha, A. K., Ruderman, N. B., & Tomas, E. (2006). Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am J Physiol Endocrinol Metab, 291(1), E175-181. doi:10.1152/ajpendo.00453.2005
Lee, S.-j., & Lee, K.-W. (2007). Protective effect of (−)-epigallocatechin gallate against advanced glycation endproducts-induced injury in neuronal cells. Biological and Pharmaceutical Bulletin, 30(8), 1369-1373.
Leick, L., Wojtaszewski, J. F., Johansen, S. T., Kiilerich, K., Comes, G., Hellsten, Y., . . . Pilegaard, H. (2008). PGC-1alpha is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle. Am J Physiol Endocrinol Metab, 294(2), E463-474. doi:10.1152/ajpendo.00666.2007
Liu, H.-W., & Chang, S.-J. (2018). Moderate exercise suppresses NF-κB signaling and activates the SIRT1-AMPK-PGC1a axis to attenuate muscle loss in diabetic db/db mice. Frontiers in Physiology, 9, 636.
Liu, Y., Dentin, R., Chen, D., Hedrick, S., Ravnskjaer, K., Schenk, S., . . . Montminy, M. (2008). A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature, 456(7219), 269-273. doi:10.1038/nature07349
Massy, Z. A., Guijarro, C., O’Donnell, M. P., Kim, Y., Kashtan, C. E., Egido, J., . . . Keane, W. F. (1999). The central role of nuclear factor-κB in mesangial cell activation. Kidney International, 56, S76-S79. doi:10.1046/j.1523-1755.1999.07119.x
Mishra, R., Emancipator, S. N., Kern, T., & Simonson, M. S. (2005). High glucose evokes an intrinsic proapoptotic signaling pathway in mesangial cells. Kidney Int, 67(1), 82-93. doi:10.1111/j.1523-1755.2005.00058.x
Mizutani, K., Ikeda, K., & Yamori, Y. (2000). Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Biochemical and biophysical research communications, 274(1), 61-67.
Mogensen, C., Christensen, C., & Vittinghus, E. (1983). The stages in diabetic renal disease: with emphasis on the stage of incipient diabetic nephropathy. Diabetes, 32(Supplement 2), 64-78.
Moien-Afshari, F., Ghosh, S., Elmi, S., Khazaei, M., Rahman, M. M., Sallam, N., & Laher, I. (2008). Exercise restores coronary vascular function independent of myogenic tone or hyperglycemic status in db/db mice. Am J Physiol Heart Circ Physiol, 295(4), H1470-1480. doi:10.1152/ajpheart.00016.2008
Moien-Afshari, F., Ghosh, S., Elmi, S., Rahman, M. M., Sallam, N., Khazaei, M., . . . Laher, I. (2008). Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice. Diabetologia, 51(7), 1327-1337. doi:10.1007/s00125-008-0996-x
Moon, J. Y., Woo, J. S., Seo, J. W., Lee, A., Kim, D. J., Kim, Y. G., . . . Kim, W. (2016). The Dose-Dependent Organ-Specific Effects of a Dipeptidyl Peptidase-4 Inhibitor on Cardiovascular Complications in a Model of Type 2 Diabetes. PLoS One, 11(3), e0150745. doi:10.1371/journal.pone.0150745
Ozkaya, D., Naziroglu, M., Armagan, A., Demirel, A., Koroglu, B. K., Colakoglu, N., . . . Sonmez, T. T. (2011). Dietary vitamin C and E modulates oxidative stress induced-kidney and lens injury in diabetic aged male rats through modulating glucose homeostasis and antioxidant systems. Cell Biochem Funct, 29(4), 287-293. doi:10.1002/cbf.1749
Persson, M. F., Franzen, S., Catrina, S. B., Dallner, G., Hansell, P., Brismar, K., & Palm, F. (2012). Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes. Diabetologia, 55(5), 1535-1543. doi:10.1007/s00125-012-2469-5
Piwkowska, A., Rogacka, D., Jankowski, M., Dominiczak, M. H., Stepinski, J. K., & Angielski, S. (2010). Metformin induces suppression of NAD(P)H oxidase activity in podocytes. Biochem Biophys Res Commun, 393(2), 268-273. doi:10.1016/j.bbrc.2010.01.119
Rosca, M. G., Mustata, T. G., Kinter, M. T., Ozdemir, A. M., Kern, T. S., Szweda, L. I., . . . Weiss, M. F. (2005). Glycation of mitochondrial proteins from diabetic rat kidney is associated with excess superoxide formation. American Journal of Physiology-Renal Physiology, 289(2), F420-F430.
Seale, P., Kajimura, S., Yang, W., Chin, S., Rohas, L. M., Uldry, M., . . . Spiegelman, B. M. (2007). Transcriptional control of brown fat determination by PRDM16. Cell Metab, 6(1), 38-54. doi:10.1016/j.cmet.2007.06.001
Siwy, J., Zoja, C., Klein, J., Benigni, A., Mullen, W., Mayer, B., . . . Bahlmann, F. H. (2012). Evaluation of the Zucker diabetic fatty (ZDF) rat as a model for human disease based on urinary peptidomic profiles. PLoS One, 7(12), e51334. doi:10.1371/journal.pone.0051334
Sriwijitkamol, A., Ivy, J. L., Christ-Roberts, C., DeFronzo, R. A., Mandarino, L. J., & Musi, N. (2006). LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training. Am J Physiol Endocrinol Metab, 290(5), E925-932. doi:10.1152/ajpendo.00429.2005
Stefanska, B. (2012). Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus–insights into its mechanisms of action. British journal of pharmacology, 166(8), 2209-2211.
Stevens, M. J., Obrosova, I., Cao, X., Van Huysen, C., & Greene, D. A. (2000). Effects of DL-alpha-lipoic acid on peripheral nerve conduction, blood flow, energy metabolism, and oxidative stress in experimental diabetic neuropathy. Diabetes, 49(6), 1006-1015.
Suwa, M., Nakano, H., Radak, Z., & Kumagai, S. (2008). Endurance exercise increases the SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1alpha protein expressions in rat skeletal muscle. Metabolism, 57(7), 986-998. doi:10.1016/j.metabol.2008.02.017
Terada, S., Goto, M., Kato, M., Kawanaka, K., Shimokawa, T., & Tabata, I. (2002). Effects of low-intensity prolonged exercise on PGC-1 mRNA expression in rat epitrochlearis muscle. Biochemical and biophysical research communications, 296(2), 350-354.
Wolf, C. M., Moskowitz, I. P., Arno, S., Branco, D. M., Semsarian, C., Bernstein, S. A., . . . Fishman, G. (2005). Somatic events modify hypertrophic cardiomyopathy pathology and link hypertrophy to arrhythmia. Proceedings of the National Academy of Sciences of the United States of America, 102(50), 18123-18128.
Yacoub, R., Lee, K., & He, J. C. (2014). The Role of SIRT1 in Diabetic Kidney Disease. Front Endocrinol (Lausanne), 5, 166. doi:10.3389/fendo.2014.00166
Zhong, X., Xiu, L. L., Wei, G. H., Liu, Y. Y., Su, L., Cao, X. P., . . . Xiao, H. P. (2011). Bezafibrate enhances proliferation and differentiation of osteoblastic MC3T3-E1 cells via AMPK and eNOS activation. Acta Pharmacol Sin, 32(5), 591-600. doi:10.1038/aps.2011.15
Zhou, G., Myers, R., Li, Y., Chen, Y., Shen, X., Fenyk-Melody, J., . . . Moller, D. E. (2001). Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest, 108(8), 1167-1174. doi:10.1172/JCI13505