Changes in Renal Glucose Transporters in an Animal Model of Metabolic Syndrome

Abstract

Considering the similarity between structural, hemodynamic, and functional changes of obesity-related renal disease and diabetic nephropathy, we hypothesized that renal glucose transporter changes occur in obesity as in diabetes. The aim of the work was to evaluate GLUT1 and GLUT2 in kidneys of an animal model of metabolic syndrome. Neonate spontaneously hypertensive rats (SHR), n=15/group, were treated with monosodium glutamate (5 mg/g) (MetS) for 9 days and compared with saline-treated Wistar-Kyoto (C) and SHR (H) rats. Lee index, systolic arterial pressure (SAP), glycemia, insulin resistance, triglycerides, and HDL cholesterol were evaluated at 3 and 6 months. Medullar GLUT1 and cortical GLUT2 were analyzed by Western blot. MetS vs. C and H rats had the highest Lee index (p<0.001) and insulin resistance (3-months C: 4.3±0.7, H: 3.9±0.9, MetS: 2.7±0.6; 6-months C: 4.2±0.6, H: 3.8±0.5, MetS: 2.4±0.6% · min⁻¹, p<0.001), similar glycemia, and the lowest HDL-cholesterol at 6-months (p<0.001). In the MetS and H rats, SAP was higher vs. C at 3-months (p<0.001) and 6-months (C: 151±15, H: 190±11, MetS: 185±13 mm Hg, p<0.001) of age. GLUT1 was ̴ 13× lower (p<0.001) at 3-months, reestablishing its content at 6-months in MetS group, while GLUT2 was 2× higher (p<0.001) in this group at 6-months of age. Renal GLUT1 and GLUT2 are modulated in kidney of rats with metabolic syndrome, where obesity, insulin resistance and hypertension coexist, despite normoglycemia. Like in diabetes, cortical GLUT2 overexpression may contribute to the development of kidney disease.

Key words

metabolic syndrome - glucose transporters - SHR - monosodium glutamate

• References

• 1 Munkhaugen J, Lydersen S, Wideroe TE, Hallan S. Prehypertension, obesity, and risk of kidney disease: 20-year follow-up of the HUNT I study in Norway. Am J Kidney Dis 2009; 54: 638-646
• 2 Vivante A, Golan E, Tzur D, Leiba A, Tirosh A, Skorecki K, Calderon-Margalit R. Body Mass Index in 1.2 Million Adolescents and Risk for End-Stage Renal Disease. Arch Intern Med 2012; 1-7
• 3 Serra A, Romero R, Lopez D, Navarro M, Esteve A, Perez N, Alastrue A, Ariza A. Renal injury in the extremely obese patients with normal renal function. Kidney Int 2008; 73: 947-955
• 4 Chagnac A, Herman M, Zingerman B, Erman A, Rozen-Zvi B, Hirsh J, Gafter U. Obesity-induced glomerular hyperfiltration: its involvement in the pathogenesis of tubular sodium reabsorption. Nephrol Dial Transplant 2008; 23: 3946-3952
• 5 Goumenos DS, Kawar B, El Nahas M, Conti S, Wagner B, Spyropoulos C, Vlachojannis JG, Benigni A, Kalfarentzos F. Early histological changes in the kidney of people with morbid obesity. Nephrol Dial Transplant 2009; 24: 3732-3738
• 6 Hunley TE, Ma LJ, Kon V. Scope and mechanisms of obesity-related renal disease. Curr Opin Nephrol Hypertens 2010; 19: 227-234
• 7 da Silva Mattos AM, Xavier CH, Karlen-Amarante M, da Cunha NV, Fontes MA, Martins-Pinge MC. Renal sympathetic nerve activity is increased in monosodium glutamate induced hyperadipose rats. Neurosci Lett 2012; 522: 118-122
• 8 D’Agord Schaan B, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H. Increased renal GLUT1 abundance and urinary TGF-beta 1 in streptozotocin-induced diabetic rats: implications for the development of nephropathy complicating diabetes. Horm Metab Res 2001; 33: 664-669
• 9 Schaan BD, Irigoyen MC, Bertoluci MC, Lima NG, Passaglia J, Hermes E, Oliveira FR, Okamoto M, Machado UF. Increased urinary TGF-beta1 and cortical renal GLUT1 and GLUT2 levels: additive effects of hypertension and diabetes. Nephron Physiol 2005; 100: 43-50
• 10 Vestri S, Okamoto MM, de Freitas HS, Aparecida Dos Santos R, Nunes MT, Morimatsu M, Heimann JC, Machado UF. Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol 2001; 182: 105-112
• 11 Freitas HS, D’Agord Schaan B, da Silva RS, Okamoto MM, Oliveira-Souza M, Machado UF. Insulin but not phlorizin treatment induces a transient increase in GLUT2 gene expression in the kidney of diabetic rats. Nephron Physiol 2007; 105: 42-51
• 12 Schaan BD, Irigoyen MC, Lacchini S, Moreira ED, Schmid H, Machado UF. Sympathetic modulation of the renal glucose transporter GLUT2 in diabetic rats. Auton Neurosci 2005; 117: 54-61
• 13 Zhang J, Liu Z, Liu D, Li L. Identification of glucose transporter-1 and its functional assay in mouse glomerular mesangial cells cultured in vitro. Chin Med Sci J 2001; 16: 35-39
• 14 Li Y, Liu Z, Liu D, Zhang J, Chen Z, Li L. Identification and function of glucose transporter 1 in human mesangial cells. Chin Med J (Engl) 2001; 114: 824-828
• 15 Bernardis LL, Patterson BD. Correlation between ‛Lee index’ and carcass fat content in weanling and adult female rats with hypothalamic lesions. J Endocrinol 1968; 40: 527-528
• 16 Mori RC, Hirabara SM, Hirata AE, Okamoto MM, Machado UF. Glimepiride as insulin sensitizer: increased liver and muscle responses to insulin. Diabetes Obes Metab 2008; 10: 596-600
• 17 Rencurel F, Waeber G, Antoine B, Rocchiccioli F, Maulard P, Girard J, Leturque A. Requirement of glucose metabolism for regulation of glucose transporter type 2 (GLUT2) gene expression in liver. Biochem J 1996; 314 (Pt 3) 903-909
• 18 Freitas HS, Schaan BD, David-Silva A, Sabino-Silva R, Okamoto MM, Alves-Wagner AB, Mori RC, Machado UF. SLC2A2 gene expression in kidney of diabetic rats is regulated by HNF-1alpha and HNF-3beta. Mol Cell Endocrinol 2009; 305: 63-70
• 19 Nguyen MT, Satoh H, Favelyukis S, Babendure JL, Imamura T, Sbodio JI, Zalevsky J, Dahiyat BI, Chi NW, Olefsky JM. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 2005; 280: 35361-35371
• 20 Leguisamo NM, Lehnen AM, Machado UF, Okamoto MM, Markoski MM, Pinto GH, Schaan BD. GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome. Cardiovasc Diabetol 2012; 11: 100
• 21 Bae JH, Bassenge E, Kim KB, Kim YN, Kim KS, Lee HJ, Moon KC, Lee MS, Park KY, Schwemmer M. Postprandial hypertriglyceridemia impairs endothelial function by enhanced oxidant stress. Atherosclerosis 2001; 155: 517-523
• 22 Kotur-Stevuljevic J, Peco-Antic A, Spasic S, Stefanovic A, Paripovic D, Kostic M, Vasic D, Vujovic A, Jelic-Ivanovic Z, Spasojevic-Kalimanovska V, Kornic-Ristovski D. Hyperlipidemia, oxidative stress, and intima media thickness in children with chronic kidney disease. Pediatr Nephrol 2013; 28: 295-303
• 23 Vulin AI, Stanley FM. Oxidative stress activates the plasminogen activator inhibitor type 1 (PAI-1) promoter through an AP-1 response element and cooperates with insulin for additive effects on PAI-1 transcription. J Biol Chem 2004; 279: 25172-25178
• 24 Im SS, Kang SY, Kim SY, Kim HI, Kim JW, Kim KS, Ahn YH. Glucose-stimulated upregulation of GLUT2 gene is mediated by sterol response element-binding protein-1c in the hepatocytes. Diabetes 2005; 54: 1684-1691
• 25 Lehnen AM, Leguisamo NM, Casali KR, Schaan BD. Progressive cardiovascular autonomic dysfunction in rats with evolving metabolic syndrome. Auton Neurosci 2013; 176: 64-69
• 26 Seraphim PM, Nunes MT, Giannocco G, Machado UF. Age related obesity-induced shortening of GLUT4 mRNA poly(A) tail length in rat gastrocnemius skeletal muscle. Mol Cell Endocrinol 2007; 276: 80-87
• 27 Jordan SD, Kruger M, Willmes DM, Redemann N, Wunderlich FT, Bronneke HS, Merkwirth C, Kashkar H, Olkkonen VM, Bottger T, Braun T, Seibler J, Bruning JC. Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat Cell Biol 2011; 13: 434-446
• 28 Trakooljul N, Hicks JA, Liu HC. Identification of target genes and pathways associated with chicken microRNA miR-143. Anim Genet 2010; 41: 357-364
• 29 Marks J, Carvou NJ, Debnam ES, Srai SK, Unwin RJ. Diabetes increases facilitative glucose uptake and GLUT2 expression at the rat proximal tubule brush border membrane. J Physiol 2003; 553: 137-145
• 30 de Carvalho Papa P, Vargas AM, da Silva JL, Nunes MT, Machado UF. GLUT4 protein is differently modulated during development of obesity in monosodium glutamate-treated mice. Life Sci 2002; 71: 1917-1928