Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice

Kim,Dal; Lee,Jung  Eun; Jung,Yu  Jin; Lee,Ae  Sin; Lee,Sik; Park,Sung  Kwang; Kim,Suhn  Hee; Park,Byung-Hyun; Kim,Won; Kang,Kyung   Pyo

doi:10.3892/ijmm.2013.1508

Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice

Authors:
- Dal Kim
- Jung Eun Lee
- Yu Jin Jung
- Ae Sin Lee
- Sik Lee
- Sung Kwang Park
- Suhn Hee Kim
- Byung-Hyun Park
- Won Kim
- Kyung Pyo Kang
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Affiliations: Department of Internal Medicine, Research Institute of Clinical Medicine and Diabetes Research Center, Chonbuk National University Medical School, Deokjin-gu, Jeonju 561-712, Republic of Korea, Department of Physiology and Diabetes, Chonbuk National University Medical School, Deokjin-gu, Jeonju 561-712, Republic of Korea, Department of Biochemistry and Diabetes Research Center, Chonbuk National University Medical School, Deokjin-gu, Jeonju 561-712, Republic of Korea
Published online on: September 25, 2013 https://doi.org/10.3892/ijmm.2013.1508
Pages: 1293-1302

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Abstract

Metabolic syndrome is characterized by insulin resistance, dyslipidemia and hypertension. These metabolic changes contribute to the development of obesity-induced kidney injury. AMP-activated protein kinase (AMPK) is a ubiquitous enzyme that is involved in the cellular metabolic response to metabolic stress. Metformin, an AMPK activator, has been reported to exert a protective effect against non-alcoholic steatohepatitis. However, little is known about its role in the pathogenesis of obesity-induced renal injury. The aim of this study was to investigate the effects of metformin on high-fat diet (HFD)-induced kidney injury. Obesity was induced by HFD (60% of total calories from fat, 20% protein and 20% carbohydrates) in 6-week-old C57BL/6 mice. Mice were fed HFD plus 0.5% metformin. The effects of metformin on HFD-induced renal injury were evaluated by determining metabolic parameters, serum adipokine levels and renal AMPK/acetyl-CoA carboxylase (ACC) activities, as well as a histological examination. HFD induced metabolic derangement, systemic insulin resistance and glomerular mesangial matrix expansion. The administration of metformin reduced HFD-induced metabolic derangement and renal injury. The administration of metformin reduced the HFD-induced increase in adipokine expression and macrophage infiltration. Moreover, renal AMPK activity, which was decreased by HFD, was recovered following the administration of metformin; in addition, fatty acid oxidation was increased by the inhibition of ACC. These results indicate that metformin exerts beneficial effects on obesity-induced renal injury by regulating systemic inflammation, insulin resistance and the renal AMPK/ACC pathway. The clinical application of metformin to obese or early diabetic patients may be helpful in preventing obesity- or diabetes-related kidney disease.

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1	Bagby SP: Obesity-initiated metabolic syndrome and the kidney: a recipe for chronic kidney disease? J Am Soc Nephrol. 15:2775–2791. 2004. View Article : Google Scholar : PubMed/NCBI
2	Chen J, Muntner P, Hamm LL, et al: Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol. 14:469–477. 2003. View Article : Google Scholar : PubMed/NCBI
3	Chen J, Muntner P, Hamm LL, et al: The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med. 140:167–174. 2004. View Article : Google Scholar : PubMed/NCBI
4	Agrawal V, Shah A, Rice C, Franklin BA and McCullough PA: Impact of treating the metabolic syndrome on chronic kidney disease. Nat Rev Nephrol. 5:520–528. 2009. View Article : Google Scholar : PubMed/NCBI
5	Maury E and Brichard SM: Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Mol Cell Endocrinol. 314:1–16. 2010. View Article : Google Scholar : PubMed/NCBI
6	Tang J, Yan H and Zhuang S: Inflammation and oxidative stress in obesity-related glomerulopathy. Int J Nephrol. 2012:6083972012.PubMed/NCBI
7	Towler MC and Hardie DG: AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res. 100:328–341. 2007. View Article : Google Scholar : PubMed/NCBI
8	Nathan DM, Buse JB, Davidson MB, et al: Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 32:193–203. 2009. View Article : Google Scholar
9	Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M and Andreelli F: Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 122:253–270. 2012. View Article : Google Scholar : PubMed/NCBI
10	El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M and Leverve X: Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 275:223–228. 2000. View Article : Google Scholar : PubMed/NCBI
11	Owen MR, Doran E and Halestrap AP: Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 348:607–614. 2000. View Article : Google Scholar : PubMed/NCBI
12	Salminen A, Hyttinen JM and Kaarniranta K: AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med (Berl). 89:667–676. 2011.
13	Zhou G, Myers R, Li Y, et al: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 108:1167–1174. 2001. View Article : Google Scholar : PubMed/NCBI
14	Viollet B, Guigas B, Leclerc J, et al: AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf). 196:81–98. 2009. View Article : Google Scholar : PubMed/NCBI
15	Abu-Elheiga L, Matzuk MM, Abo-Hashema KA and Wakil SJ: Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science. 291:2613–2616. 2001. View Article : Google Scholar : PubMed/NCBI
16	Decleves AE, Mathew AV, Cunard R and Sharma K: AMPK mediates the initiation of kidney disease induced by a high-fat diet. J Am Soc Nephrol. 22:1846–1855. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kita Y, Takamura T, Misu H, et al: Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis. PLoS One. 7:e430562012. View Article : Google Scholar : PubMed/NCBI
18	Lane PH, Steffes MW and Mauer SM: Estimation of glomerular volume: a comparison of four methods. Kidney Int. 41:1085–1089. 1992.PubMed/NCBI
19	Kim DH, Jung YJ, Lee AS, et al: COMP-angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury. Kidney Int. 76:1180–1191. 2009. View Article : Google Scholar : PubMed/NCBI
20	Kang KP, Kim DH, Jung YJ, et al: Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol Dial Transplant. 24:3012–3020. 2009. View Article : Google Scholar : PubMed/NCBI
21	Kang KP, Park SK, Kim DH, et al: Luteolin ameliorates cisplatin-induced acute kidney injury in mice by regulation of p53-dependent renal tubular apoptosis. Nephrol Dial Transplant. 26:814–822. 2011. View Article : Google Scholar : PubMed/NCBI
22	Dengel DR, Goldberg AP, Mayuga RS, Kairis GM and Weir MR: Insulin resistance, elevated glomerular filtration fraction, and renal injury. Hypertension. 28:127–132. 1996. View Article : Google Scholar : PubMed/NCBI
23	Henegar JR, Bigler SA, Henegar LK, Tyagi SC and Hall JE: Functional and structural changes in the kidney in the early stages of obesity. J Am Soc Nephrol. 12:1211–1217. 2001.PubMed/NCBI
24	Wolf G, Hamann A, Han DC, et al: Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis [see comments]. Kidney Int. 56:860–872. 1999.PubMed/NCBI
25	Han DC, Isono M, Chen S, et al: Leptin stimulates type I collagen production in db/db mesangial cells: glucose uptake and TGF-beta type II receptor expression. Kidney Int. 59:1315–1323. 2001. View Article : Google Scholar : PubMed/NCBI
26	Chudek J, Adamczak M, Nieszporek T and Wiecek A: The adipose tissue as an endocrine organ - a nephrologists’ perspective. Contrib Nephrol. 151:70–90. 2006.PubMed/NCBI
27	Diez JJ and Iglesias P: The role of the novel adipocyte-derived hormone adiponectin in human disease. Eur J Endocrinol. 148:293–300. 2003. View Article : Google Scholar : PubMed/NCBI
28	Sharma K, Ramachandrarao S, Qiu G, et al: Adiponectin regulates albuminuria and podocyte function in mice. J Clin Invest. 118:1645–1656. 2008.PubMed/NCBI
29	Ix JH and Sharma K: Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol. 21:406–412. 2010. View Article : Google Scholar : PubMed/NCBI
30	Deen WM: What determines glomerular capillary permeability? J Clin Invest. 114:1412–1414. 2004. View Article : Google Scholar : PubMed/NCBI
31	Mundel P, Heid HW, Mundel TM, Kruger M, Reiser J and Kriz W: Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol. 139:193–204. 1997. View Article : Google Scholar : PubMed/NCBI
32	Ghayur A, Liu L, Kolb M, et al: Adenovirus-mediated gene transfer of TGF-beta1 to the renal glomeruli leads to proteinuria. Am J Pathol. 180:940–951. 2012. View Article : Google Scholar : PubMed/NCBI
33	Bobulescu IA: Renal lipid metabolism and lipotoxicity. Curr Opin Nephrol Hypertens. 19:393–402. 2010. View Article : Google Scholar
34	Bailey CJ and Turner RC: Metformin. N Engl J Med. 334:574–579. 1996. View Article : Google Scholar : PubMed/NCBI