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http://dx.doi.org/10.5352/JLS.2015.25.4.463

Adrenomedullin Deficiency Increases the Susceptibility of Liver Fibrosis Induced by CCl4  

Ji, Ae-Ri (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Hwang, Meeyul (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Kim, Ah-Young (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Lee, Eun-Mi (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Lee, Eun-Joo (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Lee, Myeong-Mi (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Sung, Soo-Eun (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Kim, Sang-Hyeob (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Park, Jin-Kyu (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Jeong, Kyu-Shik (Department of Pathology, College of Veterinary Medicine, Kyungpook National University)
Publication Information
Journal of Life Science / v.25, no.4, 2015 , pp. 463-472 More about this Journal
Abstract
Adrenomedullin (AM) is a peptide expressed in all body tissues, and its related receptors are increased in liver fibrosis. In this study, we evaluated the effect of AM deficiency on liver fibrogenesis induced by $CCl_4$ using AM heterozygous (HT) mice. The animals received a single injection of $CCl_4$ or olive oil for the acute experiment, and received $CCl_4$ or olive oil three times a week for 6 weeks for the chronic experiment. Fibrosis was accessed using histopathological analysis and the western blot. The AM HT mice showed mild pericentrilobular degeneration when compared to the AM wild type (WT) mice. In the acute experiment, there was no significant difference between the AM WT and AM HT mice. However, in the chronic experiment, the $CCl_4$-treated AM HT mice showed more severe liver fibrosis than that of the CCl4-treated AM WT mice. The AST and ALT levels of the AM HT $CCl_4$ group were higher than those of the AM WT CCl4 group. Additionally, the collagen deposition, $\alpha$- SMA protein and TGF-$\beta$ protein were increased in the AM HT $CCl_4$ group when compared to the AM WT $CCl_4$ group. The AM HT mice also exhibited severe lipid peroxidation through the GSH decrement. Taken together, our data suggest that AM deficiency increases the susceptibility to liver fibrosis induced by $CCl_4$, indicating a novel therapeutic target for patients with liver fibrosis.
Keywords
Adrenomedullin; lipid peroxidation; liver fibrosis; TGF-$\beta$;
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1 Garayoa, M., Martínez, A., Lee, S., Pío, R., An, W. G., Neckers, L., Trepel, J., Montuenga, L. M., Ryan. H., Johnson, R., Gassmann, M. and Cuttitta, F. 2000. Hypoxia-inducible factor-1 (HIF-1) up-regulates adrenomedullin expression in human tumor cell lines during oxygen deprivation: a possible promotion mechanism of carcinogenesis. Mol. Endocrinol. 14, 848-862.   DOI
2 Hinson, J. P., Kapas, S. and Smith, D. M. 2000. Adrenomedullin, a multifunctional regulatory peptide. Endocr. Rev. 21, 138-167.
3 Iimuro, S., Shindo, T., Moriyama, N., Amaki, T., Niu, P., Takeda, N., Iwata, H., Zhang, Y., Ebihara, A. and Nagai, R. 2004. Angiogenic effects of adrenomedullin in ischemia and tumor growth. Circ. Res. 95, 415-423.   DOI
4 Kaplowitz, N. J. 2000. Mechanisms of liver cell injury. Hepatology 32, 39-47.
5 Kim, J. Y., Yim, J. H., Cho, J. H., Kim, J. H., Ko, J. H., Kim, S. M., Park, S. and Park, J. H. 2006. Adrenomedullin regulates cellular glutathione content via modulation of gamma-glutamate-cysteine ligase catalytic subunit expression. Endocrinology 147, 1357-1364.   DOI
6 Kim, S. M., Kim, J. Y., Lee, S. and Park, J. H. 2010. Adrenomedullin protects against hypoxia/reoxygenation-induced cell death by suppression of reactive oxygen species via thiol redox systems. FEBS Lett. 584, 213-218.   DOI
7 Matsuoka, J., Yashiro, M., Doi, Y., Fuyuhiro, Y., Kato, Y., Shinto, O., Noda, S., Kashiwagi, S., Aomatsu, N., Hirakawa, T., Hasegawa, T., Shimizu, K., Shimizu, T., Miwa, A., Yamada, N., Sawada, T. and Hirakawa, K. 2013. Hypoxia stimulates the EMT of gastric cancer cells through autocrine TGF-β signaling. PLoS ONE 8, e62310. doi:10.1371/journal.pone.0062310   DOI
8 Kim, W., Moon, S. O., Sung, M. J., Kim, S. H., Lee, S., So, J. N. and Park, S. K. 2003. Angiogenic role of adrenomedullin through activation of Akt, mitogen-activated protein kinase, and focal adhesion kinase in endothelial cells. FASEB J. 17, 1937-1939.
9 Liu, Y., Zhao, H., Li, H., Kalyanaraman, B., Nicolosi, A. C. and Gutterman, D. D. 2003. Mitochondrial sources of H2O2 generation play a key role in flow-mediated dilation in human coronary resistance arteries. Circ. Res. 93, 573-580.   DOI
10 Malhi, H. and Gores, G. J. 2008. Cellular and molecular mechanisms of liver injury. Gastroenterology 134, 1641-1654.   DOI
11 Mendler, M. H., Kanel, G. and Govindarajan, S. 2005. Proposal for a histological scoring and grading system for non-alcoholic fatty liver disease. Liver Int. 25, 294-304.   DOI
12 Odena, G. and Bataller, R. 2012. Liver fibrogenesis: physiopathology. Gastroenterol. Hepatology 2, 3-9.
13 Onur, O. E., Guneysel, O., Akoglu, H., Denizbasi, A. and Onur, E. 2007. Adrenomedullin reduces the severity of cerulein-induced acute pancreatitis. Peptides 28, 2179-2183.   DOI
14 Pandey, A. and Katiyar, S. S. 1996. Inactivation of yeast glutathione reductase by O-phthalaldehyde. J. Enzyme Inhib. 11, 141-149.   DOI
15 Schafer, F. Q. and Buettner, G. R. 2001. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic. Biol. Med. 30, 1191-1212.   DOI
16 Paravicini, T. M., Chrissobolis, S., Drummond, G. R. and Sobey, C. G. 2004. Increased NADPH-oxidase activity and Nox4 expression during chronic hypertension is associated with enhanced cerebral vasodilatation to NADPH in vivo. Stroke 35, 584-589.   DOI
17 Shimosawa, T., Matsui, H., Xing, G., Itakura, K., Ando, K. and Fujita, T. 2003. Organ-protective effects of adrenomedullin. Hypertens. Res. 26, S109-112.   DOI
18 Parola, M., Pinzani, M., Casini, A., Albano, E., Poli, G., Gentilini, A., Gentilini, P. and Dianzani, M. U. 1993. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells. Biochem. Biophys. Res. Commun. 194, 1044-1050.   DOI
19 Sakimoto, S., Kidoya, H., Kamei, M., Naito, H., Yamakawa, D., Sakaguchi, H., Wakabayashi, T., Nishida, K. and Takakura, N. 2013. An angiogenic role for adrenomedullin in choroidal neovascularization. PLoS One 8, e58096.   DOI
20 Schiffrin, E. L. and Touyz, R. M. 2004. From bedside to bench to bedside: role of renin-angiotensin-aldosterone system in remodeling of resistance arteries in hypertension. Am. J. Physiol. Heart Circ. Physiol. 287, H435-46.   DOI   ScienceOn
21 Shindo, T., Kurihara, Y., Nishimatsu, H., Moriyama, N., Kakoki, M., Wang, Y., Imai, Y., Ebihara, A., Kuwaki, T., Ju, K. H., Minamino, N., Kangawa, K., Ishikawa, T., Fukuda, M., Akimoto, Y., Kawakami, H., Imai, T., Morita, H., Yazaki, Y., Nagai, R., Hirata, Y. and Kurihara, H. 2001. Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene. Circulation 104, 1964-1971.   DOI
22 Weber, L. W., Boll, M. and Stampfl, A. 2003. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit. Rev. Toxicol. 33, 105-136.   DOI
23 Chini, E. N., Chini, C. C., Bolliger, C., Jougasaki, M., Grande, J. P., Burnett, J. C. Jr. and Dousa, T. P. 1997. Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway. Kidney Int. 52, 917-925.   DOI
24 Haouzi, D., Lekéhal, M., Moreau, A., Moulis, C., Feldmann, G., Robin, M. A., Lettéron, P., Fau, D. and Pessayre, D. 2000. Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes. Hepatology 32, 303-311.   DOI
25 Alonso-Galicia, M. and Drummond, H. A. 1997. Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide. Hypertension 29, 320-325.   DOI
26 Biernacka, A., Dobaczewski, M. and Frangogiannis, N. G. 2011. TGF-β signaling in fibrosis. Growth Factors 29, 196-202.   DOI
27 Chojkier, M., Houglum, K., Solis-Herruzo, J. and Brenner, D. A. 1989. Stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts. A role for lipid peroxidation? J. Biol Chem. 264, 16957-16962.