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PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-β1

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Abstract

Previous studies have shown that high glucose stimulates renal SREBP-1 gene expression and increases renal tubular cells lipid metabolism, however, the mechanisms remain elusive. In the present study we demonstrated that PI3K/Akt pathway was activated in human renal proximal tubular cell line (HKC) exposed to high glucose accompanied with up-regulation of SREBP-1, TGF-β1, lipid droplets deposits and extracellular matrix production. Inhibition of PI3K/Akt pathway by chemical LY294002 or specific short hairpin RNA (shRNA) vector prevented SREBP-1 and TGF-β1 up-regulation, as well as ameliorated HKC cells lipogenesis and extracellular matrix accumulation. These findings indicate that PI3K/Akt pathway potentially mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells.

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References

  • Berndt A, Köllner R, Richter P, Franz M, Voigt A, Berndt A, Borsi L, Giavazzi R, Neri D, Kosmehl H (2010) A comparative analysis of oncofetal fibronectin and tenascin-C incorporation in tumour vessels using human recombinant SIP format antibodies. Histochem Cell Biol 133:467–475

    Article  CAS  PubMed  Google Scholar 

  • Bruss MD, Arias EB, Lienhard GE, Cartee GD (2005) Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes 54:41–50

    Article  CAS  PubMed  Google Scholar 

  • Chai Q, Krag S, Chai S, Ledet T, Wogensen L (2003) Localisation and phenotypical characterisation of collagen-producing cells in TGF-beta 1-induced renal interstitial fibrosis. Histochem Cell Biol 119:267–280

    CAS  PubMed  Google Scholar 

  • Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    Article  CAS  PubMed  Google Scholar 

  • Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509

    CAS  PubMed  Google Scholar 

  • Fujii H, Kono K, Nakai K, Goto S, Komaba H, Hamada Y, Shinohara M, Kitazawa R, Kitazawa S, Fukagawa M (2010) Oxidative and nitrosative stress and progression of diabetic nephropathy in type 2 diabetes. Am J Nephrol 31:342–352

    Article  CAS  PubMed  Google Scholar 

  • Furuta E, Pai SK, Zhan R, Bandyopadhyay S, Watabe M, Mo YY, Hirota S, Hosobe S, Tsukada T, Miura K, Kamada S, Saito K, Iiizumi M, Liu W, Ericsson J, Watabe K (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res 68:1003–1011

    Article  CAS  PubMed  Google Scholar 

  • Isoe T, Makino Y, Mizumoto K, Sakagami H, Fujita Y, Honjo J, Takiyama Y, Itoh H, Haneda M (2010) High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein. Kidney Int 78:48–59

    Article  CAS  PubMed  Google Scholar 

  • Jackel-Cram C, Qiao L, Xiang Z, Brownlie R, Zhou Y, Babiuk L, Liu Q (2010) Hepatitis C virus genotype-3a core protein enhances sterol regulatory element-binding protein-1 activity through the phosphoinositide 3-kinase-Akt-2 pathway. J Gen Virol 91:1388–1395

    Article  CAS  PubMed  Google Scholar 

  • Jiang HL, Xu CX, Kim YK, Arote R, Jere D, Lim HT, Cho MH, Cho CS (2009) The suppression of lung tumorigenesis by aerosol-delivered folate-chitosan-graft-polyethylenimine/Akt1 shRNA complexes through the Akt signaling pathway. Biomaterials 30:5844–5852

    Article  CAS  PubMed  Google Scholar 

  • Jun H, Song Z, Chen W, Zanhua R, Yonghong S, Shuxia L, Huijun D (2009) In vivo and in vitro effects of SREBP-1 on diabetic renal tubular lipid accumulation and RNAi-mediated gene silencing study. Histochem Cell Biol 131:327–345

    Article  PubMed  Google Scholar 

  • Kim JB, Spotts GD, Halvorsen YD, Shih HM, Ellenberger T, Towle HC, Spiegelman BM (1995) Dual DNA binding specificity of ADD1/SREBP1 controlled by a single amino acid in the basic helix-loop-helix domain. Mol Cell Biol 15:2582–2588

    CAS  PubMed  Google Scholar 

  • Kim YH, Ryu JM, Lee YJ, Han HJ (2010) Fibronectin synthesis by high glucose level mediated proliferation of mouse embryonic stem cells: Involvement of ANG II and TGF-beta1. J Cell Physiol 223:397–407

    CAS  PubMed  Google Scholar 

  • Li J, Kang SW, Kim JL, Sung HY, Kwun IS, Kang YH (2010) Isoliquiritigenin entails blockade of TGF-beta1-SMAD signaling for retarding high glucose-induced mesangial matrix accumulation. J Agric Food Chem 58:3205–3212

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto M, Han S, Kitamura T, Accili D (2006) Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism. J Clin Invest 116:2464–2472

    CAS  PubMed  Google Scholar 

  • Ortiz-Muñoz G, Lopez-Parra V, Lopez-Franco O, Fernandez-Vizarra P, Mallavia B, Flores C, Sanz A, Blanco J, Mezzano S, Ortiz A, Egido J, Gomez-Guerrero C (2010) Suppressors of cytokine signaling abrogate diabetic nephropathy. J Am Soc Nephrol 21:763–772

    Article  PubMed  Google Scholar 

  • Parent R, Kolippakkam D, Booth G, Beretta L (2007) Mammalian target of rapamycin activation impairs hepatocytic differentiation and targets genes moderating lipid homeostasis and hepatocellular growth. Cancer Res 67:4337–4345

    Article  CAS  PubMed  Google Scholar 

  • Park CY, Jun HJ, Wakita T, Cheong JH, Hwang SB (2009) Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway. J Biol Chem 284:9237–9246

    Article  CAS  PubMed  Google Scholar 

  • Roder K, Zhang L, Schweizer M (2007) SREBP-1c mediates the retinoid-dependent increase in fatty acid synthase promoter activity in HepG2. FEBS Lett 581:2715–2720

    Article  CAS  PubMed  Google Scholar 

  • Ryu JM, Lee MY, Yun SP, Han HJ (2010) High glucose regulates cyclin D1/E of human mesenchymal stem cells through TGF-beta1 expression via Ca2+/PKC/MAPKs and PI3K/Akt/mTOR signal pathways. J Cell Physiol 224:59–70

    CAS  PubMed  Google Scholar 

  • Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL (1996) Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 85:1037–1046

    Article  CAS  PubMed  Google Scholar 

  • Saudemont A, Colucci F (2009) PI3K signaling in lymphocyte migration. Cell Cycle 8:3307–3310

    Article  CAS  PubMed  Google Scholar 

  • Sheu ML, Ho FM, Yang RS, Chao KF, Lin WW, Lin-Shiau SY, Liu SH (2005) High glucose induces human endothelial cell apoptosis through a phosphoinositide 3-kinase-regulated cyclooxygenase-2 pathway. Arterioscler Thromb Vasc Biol 25:539–545

    Article  CAS  PubMed  Google Scholar 

  • Smith TM, Gilliland K, Clawson GA, Thiboutot D (2008) IGF-1 induces SREBP-1 expression and lipogenesis in SEB-1 sebocytes via activation of the phosphoinositide 3-kinase/Akt pathway. J Invest Dermatol 128:1286–1293

    Article  CAS  PubMed  Google Scholar 

  • Soutschek J, Akinc A, Bramlage B, Charisse K, Constien R, Donoghue M, Elbashir S, Geick A, Hadwiger P, Harborth J, John M, Kesavan V, Lavine G, Pandey RK, Racie T, Rajeev KG, Röhl I, Toudjarska I, Wang G, Wuschko S, Bumcrot D, Koteliansky V, Limmer S, Manoharan M, Vornlocher HP (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173–178

    Article  CAS  PubMed  Google Scholar 

  • Takashima M, Ogawa W, Emi A, Kasuga M (2009) Regulation of SREBP1c expression by mTOR signaling in hepatocytes. Kobe J Med Sci 55:E45–E52

    CAS  PubMed  Google Scholar 

  • Venkatachalam K, Mummidi S, Cortez DM, Prabhu SD, Valente AJ, Chandrasekar B (2008) Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts. Am J Physiol Heart Circ Physiol 294:H2078–H2087

    Article  CAS  PubMed  Google Scholar 

  • Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H–1-benzopyran-4-one (LY294002). J Biol Chem 269:5241–5248

    CAS  PubMed  Google Scholar 

  • Wu D, Peng F, Zhang B, Ingram AJ, Kelly DJ, Gilbert RE, Gao B, Kumar S, Krepinsky JC (2009) EGFR-PLCgamma1 signaling mediates high glucose-induced PKCbeta1-Akt activation and collagen I upregulation in mesangial cells. Am J Physiol Ren Physiol 297:F822–F834

    Article  CAS  Google Scholar 

  • Zhou L, Xue H, Yuan P, Ni J, Yu C, Huang Y, Lu LM (2010) Angiotensin AT1 receptor activation mediates high glucose-induced epithelial-mesenchymal transition in renal proximal tubular cells. Clin Exp Pharmacol Physiol 37:e152–e157

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by a grant from Public Health Department of Hebei Province of China (No.20090050). We thank Dr. Myung-Haing CHO for sh-Akt and sh-Scramble vectors and Dr. Chen Xiang-mei for human renal proximal tubular epithelial cell line (HKC).

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Authors and Affiliations

  1. Department of Pathology, Hebei Medical University, NO361 Zhongshan East Road, Shijiazhuang, 050017, Hebei, China

    Jun Hao, Shuxia Liu, Song Zhao, Qingjuan Liu, Xin Lv, Huan Chen, Yunyi Niu & Huijun Duan

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  1. Jun Hao
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  2. Shuxia Liu
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  3. Song Zhao
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  4. Qingjuan Liu
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  5. Xin Lv
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  6. Huan Chen
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  7. Yunyi Niu
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  8. Huijun Duan
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Correspondence to Huijun Duan.

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Hao, J., Liu, S., Zhao, S. et al. PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-β1. Histochem Cell Biol 135, 173–181 (2011). https://doi.org/10.1007/s00418-011-0777-3

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