Changes of CCAAT Enhancer-binding Proteins (CEBPs) in the Lung of Streptozotocin-induced Diabetic Rats

Abstract

CCAAT enhancer-binding proteins (CEBPs) play key roles in the metabolic regulation, cell transformation, and inflammation. However, the expression and/or functions of CEBPs in rats with hyperglycemia are still unclear. In the present study, we investigated the changes of CEBPs protein in lung of the diabetic rats. The levels of C/EBPβ and C/EBPδ protein were decreased in the lung isolated from streptozotocin-induced diabetic rats (STZ-diabetic rats) as compared with that of normal rats. Exogenous insulin at the dose sufficient to normalize the plasma glucose of STZ-diabetic rats reversed the protein levels of C/EBPβ and C/EBPδ in lung after a 4-day treatment. Similar results were also observed in STZ-diabetic rats that received the treatment of phlorizin to reverse the plasma glucose level for 4 days. Otherwise, the protein level of C/EBPα in lung of the STZ-diabetic rats was similar as the normal rats. Also, the level of C/EBPα protein in lung of the STZ-diabetic rat was not significantly changed by correction of plasma glucose by exogenous insulin or phlorizin. In addition, we also cultured human lung cells (A-549) and rat lung cells (L2) in varies concentration of D-glucose and L-glucose to identify the effect of glucose in expression of C/EBPs. The obtained results suggest that increase of plasma glucose is related to the lower expression of C/EBPβ and C/EBPδ proteins in the lung of STZ-diabetic rats. The changes of expression of C/EBPβ and C/EBPδ are not caused by changes of osmolarity but by D-glucose itself.

Key words

lung - CCAAT enhancer-binding proteins (CEBPs) - phlorizin - STZ-diabetic rats - D-glucose - L-glucose

References

• 1 Koh G, Suh KS, Chon S, Oh S, Woo JT, Kim SW, Kim JW, Kim YS. Elevated cAMP level attenuates 2-deoxy-d-ribose-induced oxidative damage in pancreatic beta-cells.  Arch Biochem Biophys. 2005;  438 70-79
• 2 Sugawara I, Yamada H, Mizuno S. Pulmonary tuberculosis in spontaneously diabetic goto kakizaki rats.  Tohoku J Exp Med. 2004;  204 135-145
• 3 Popov D, Simionescu M. Structural and transport property alterations of the lung capillary endothelium in diabetes.  Ital J Anat Embryol. 2001;  106 405-412
• 4 Ehrlich SF, Quesenberry Jr CP, Van Den Eeden SK, Shan J, Ferrara A. Patients diagnosed with diabetes are at increased risk for asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and pneumonia but not lung cancer.  Diabetes Care. 2010;  33 55-60
• 5 Innocenti F, Fabbri A, Anichini R, Tuci S, Pettina G, Vannucci F, De Giorgio LA, Seghieri G. Indications of reduced pulmonary function in type 1 (insulin-dependent) diabetes mellitus.  Diabetes Res Clin Pract. 1994;  25 161-168
• 6 Bell D, Collier DA. Transfer factor for carbon monoxide in patients with diabetes with and without microangiopathy.  Thorax. 1989;  44 446
• 7 Weir DC, Jennings PE, Hendy MS, Barnett AH, Burge PS. Transfer factor for carbon monoxide in patients with diabetes with and without microangiopathy.  Thorax. 1988;  43 725-726
• 8 Akasaka T, Balasas T, Russell LJ, Sugimoto KJ, Majid A, Walewska R, Karran EL, Brown DG, Cain K, Harder L, Gesk S, Martin-Subero JI, Atherton MG, Bruggemann M, Calasanz MJ, Davies T, Haas OA, Hagemeijer A, Kempski H, Lessard M, Lillington DM, Moore S, Nguyen-Khac F, Radford-Weiss I, Schoch C, Struski S, Talley P, Welham MJ, Worley H, Strefford JC, Harrison CJ, Siebert R, Dyer MJ. Five members of the CEBP transcription factor family are targeted by recurrent IGH translocations in B-cell precursor acute lymphoblastic leukemia (BCP-ALL).  Blood. 2007;  109 3451-3461
• 9 Lee K, Hausman GJ, Dean RG. Expression of C/EBP alpha, beta and delta in fetal and postnatal subcutaneous adipose tissue.  Mol Cell Biochem. 1998;  178 269-274
• 10 Yeh WC, Cao Z, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins.  Genes Dev. 1995;  9 168-181
• 11 Freytag SO, Paielli DL, Gilbert JD. Ectopic expression of the CCAAT/enhancer-binding protein alpha promotes the adipogenic program in a variety of mouse fibroblastic cells.  Genes Dev. 1994;  8 1654-1663
• 12 Huang CJ, Liu IM, Cheng JT. Increase of peroxisome proliferator-activated receptor delta gene expression in the lungs of streptozotocin-induced diabetic rats.  Pulm Pharmacol Ther. 2007;  20 69-74
• 13 Kudo M, Sugawara A, Uruno A, Takeuchi K, Ito S. Transcription suppression of peroxisome proliferator-activated receptor gamma2 gene expression by tumor necrosis factor alpha via an inhibition of CCAAT/enhancer-binding protein delta during the early stage of adipocyte differentiation.  Endocrinology. 2004;  145 4948-4956
• 14 Cheng JT, Huang CC, Liu IM, Tzeng TF, Chang CJ. Novel mechanism for plasma glucose-lowering action of metformin in streptozotocin-induced diabetic rats.  Diabetes. 2006;  55 819-825
• 15 Yu BC, Chang CK, Ou HY, Cheng KC, Cheng JT. Decrease of peroxisome proliferator-activated receptor delta expression in cardiomyopathy of streptozotocin-induced diabetic rats.  Cardiovasc Res. 2008;  80 78-87
• 16 Liu IM, Tzeng TF, Tsai CC, Lai TY, Chang CT, Cheng JT. Increase in adenosine A1 receptor gene expression in the liver of streptozotocin-induced diabetic rats.  Diabetes Metab Res Rev. 2003;  19 209-215
• 17 Gromova LV, Grefner NM, Gruzdkov AA, Komissarchik I. The role of facilitated diffusion in glucose transport across the apical membrane of enterocytes.  Ross Fiziol Zh Im I M Sechenova. 2006;  92 362-373
• 18 Carruthers A. Facilitated diffusion of glucose.  Physiol Rev. 1990;  70 1135-1176
• 19 Rossetti L, Smith D, Shulman GI, Papachristou D, DeFronzo RA. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats.  J Clin Invest. 1987;  79 1510-1515
• 20 Ghosh R, Karmohapatra SK, Bhattacharya G, Kumar Sinha A. The glucose-induced synthesis of insulin in liver.  Endocrine. 2010;  38 294-302
• 21 Kobayashi K, Nishioka M, Kohno T, Nakamoto M, Maeshima A, Aoyagi K, Sasaki H, Takenoshita S, Sugimura H, Yokota J. Identification of genes whose expression is upregulated in lung adenocarcinoma cells in comparison with type II alveolar cells and bronchiolar epithelial cells in vivo.  Oncogene. 2004;  23 3089-3096
• 22 Walther UI, Wilhelm B, Walther S, Muckter H, Fichtl B. Zinc toxicity in various lung cell lines is mediated by glutathione and GSSG reductase activity.  Biol Trace Elem Res. 2000;  78 163-177
• 23 Craik JD, Young JD, Cheeseman CI. GLUT-1 mediation of rapid glucose transport in dolphin (Tursiops truncatus) red blood cells.  Am J Physiol. 1998;  274 R112-R119
• 24 Joost HG, Wandel S, Schurmann A. Structure-function relationship of glucose transporters catalyzing facilitated diffusion.  Exp Clin Endocrinol. 1994;  102 434-438
• 25 Leese HJ, Jeffries KS. Evidence for the facilitated diffusion of glucose into rabbit oviductal fluid.  J Reprod Fertil. 1977;  51 93-97
• 26 Cunningham P, Afzal-Ahmed I, Naftalin RJ. Docking studies show that D-glucose and quercetin slide through the transporter GLUT1.  J Biol Chem. 2006;  281 5797-5803
• 27 Titty FK. Glycaemic Control, Dyslipidaemia and Metabolic Syndrome among Recently Diagnosed Diabetes Mellitus Patients in Tamale Teaching Hospital, Ghana.  West Afr J Med. 2010;  29 8-11
• 28 Kornum JB, Thomsen RW, Riis A, Lervang HH, Schonheyder HC, Sorensen HT. Diabetes, glycemic control, and risk of hospitalization with pneumonia: a population-based case-control study.  Diabetes Care. 2008;  31 1541-1545
• 29 Pozzilli P, Leslie RD. Infections and diabetes: mechanisms and prospects for prevention.  Diabet Med. 1994;  11 935-941
• 30 Huang AM, Rudelius M, Sharan S, McAllister JM, Raffeld M, Christenson LK, Sterneck E. The Cebpd (C/EBPdelta) gene is induced by luteinizing hormones in ovarian theca and interstitial cells but is not essential for mouse ovary function.  PLoS One. 2007;  2 e1334
• 31 Kuruto-Niwa R, Nakamura M, Takeishi K, Nozawa R. Transcriptional regulation by C/EBP alpha and -beta in the expression of the gene for the MRP14 myeloid calcium binding protein.  Cell Struct Funct. 1998;  23 109-118

1 These authors contributed equally to this study.

Correspondence