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Transcription factor 7-like 2 (TCF7L2) regulates activin receptor-like kinase 1 (ALK1)/Smad1 pathway for development of diabetic nephropathy

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Molecules and Cells

Abstract

Smad1 has previously been shown to play a key role in the development of diabetic nephropathy (DN), by increasing synthesis of extracellular matrix. However, the regulatory mechanism of Smad1 in DN is still unclear. This study aims to elucidate molecular interactions between activin receptor-like kinase 1 (ALK1)/Smad1 signaling pathway and transcription factor 7-like 2 (TCF7L2) in the progression of DN in vitro and in vivo. The expressions of TCF7L2 and ALK1 were induced by advanced glycation end products (AGEs) in parallel with Smad1, phosphorylated Smad1 (pSmad1), and alpha-smooth muscle actin (α-SMA) through TGF-β1 in cultured mesangial cells. Constitutively active ALK1 increased pSmad1 and α-SMA expressions. The binding of TCF7L2 to ALK1 promoter was confirmed by chromatin immunoprecipitation assay. Furthermore, TCF7L2 induced promoter activity of ALK1. AGEs and TGF-β1 induced a marked increase in TCF7L2 expression in parallel with ALK1. Overexpression of TCF7L2 increased the expressions of ALK1 and Smad1. Inversely, TCF7L2 knockdown by siRNA suppressed α-SMA expression as well as ALK1 and Smad1. The iNOS transgenic mice (iNOS-Tgm), which developed diabetic glomerulosclerosis resembling human diabetic nephropathy, exhibited markedly increased expressions of ALK1, TCF7L2, Smad1, pSmad1, and α-SMA in glomeruli in association with mesangial matrix expansion. These results provide a new evidence that the TCF7L2/ALK1/Smad1 pathway plays a key role in the development of DN.

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References

  • Abe, H., Matsubara, T., Iehara, N., Nagai, K., Takahashi, T., Arai, H., Kita, T., and Doi, T. (2004). Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J. Biol. Chem. 279, 14201–14206.

    Article  CAS  PubMed  Google Scholar 

  • Bojestig, M., Arnqvist, H.J., Hermansson, G., Karlberg, B.E., and Ludvigsson, J. (1994). Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N. Engl. J. Med. 330, 15–18.

    Article  CAS  PubMed  Google Scholar 

  • Davies, M. (1994). The mesangial cell: a tissue culture view. Kidney Int. 45, 320–327.

    Article  CAS  PubMed  Google Scholar 

  • Doi, T., Vlassara, H., Kirstein, M., Yamada, Y., Striker, G.E., and Striker, L.J. (1992). Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc. Natl. Acad. Sci. USA 89, 2873–2877.

    Article  CAS  PubMed  Google Scholar 

  • Elbein, S.C., Das, S.K., Hallman, D.M., Hanis, C.L., and Hasstedt, S.J. (2009). Genome-wide linkage and admixture mapping of type 2 diabetes in African American families from the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort. Diabetes 58, 268–274.

    Article  CAS  PubMed  Google Scholar 

  • Essawy, M., Soylemezoglu, O., Muchaneta-Kubara, E.C., Shortland, J., Brown, C.B., and el Nahas, A.M. (1997). Myofibroblasts and the progression of diabetic nephropathy. Nephrol. Dial. Transplant 12, 43–50.

    Article  CAS  PubMed  Google Scholar 

  • Fink, L., Seeger, W., Ermert, L., Hanze, J., Stahl, U., Grimminger, F., Kummer, W., and Bohle, R.M. (1998). Real-time quantitative RT-PCR after laser-assisted cell picking. Nat. Med. 4, 1329–1333.

    Article  CAS  PubMed  Google Scholar 

  • Finnson, K.W., Parker, W.L., ten Dijke, P., Thorikay, M., and Philip, A. (2008). ALK1 opposes ALK5/Smad3 signaling and expression of extracellular matrix components in human chondrocytes. J. Bone Miner. Res. 23, 896–906.

    Article  CAS  PubMed  Google Scholar 

  • Florez, J.C., Jablonski, K.A., Bayley, N., Pollin, T.I., de Bakker, P.I., Shuldiner, A.R., Knowler, W.C., Nathan, D.M., and Altshuler, D. (2006). TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N. Engl. J. Med. 355, 241–250.

    Article  CAS  PubMed  Google Scholar 

  • Gerstein, H.C., Mann, J.F., Yi, Q., Zinman, B., Dinneen, S.F., Hoogwerf, B., Halle, J.P., Young, J., Rashkow, A., Joyce, C., et al. (2001). Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 286, 421–426.

    Article  CAS  PubMed  Google Scholar 

  • Go, A.S., Chertow, G.M., Fan, D., McCulloch, C.E., and Hsu, C.Y. (2004). Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305.

    Article  CAS  PubMed  Google Scholar 

  • Goumans, M.J., Valdimarsdottir, G., Itoh, S., Rosendahl, A., Sideras, P., and ten Dijke, P. (2002). Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 21, 1743–1753.

    Article  CAS  PubMed  Google Scholar 

  • Grant, S.F., Thorleifsson, G., Reynisdottir, I., Benediktsson, R., Manolescu, A., Sainz, J., Helgason, A., Stefansson, H., Emilsson, V., Helgadottir, A., et al. (2006). Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38, 320–323.

    Article  CAS  PubMed  Google Scholar 

  • Hautmann, M.B., Madsen, C.S., and Owens, G.K. (1997). A transforming growth factor beta (TGFbeta) control element drives TGFbeta-induced stimulation of smooth muscle alpha-actin gene expression in concert with two CArG elements. J. Biol. Chem. 272, 10948–10956.

    Article  CAS  PubMed  Google Scholar 

  • Inman, G.J., Nicolas, F.J., Callahan, J.F., Harling, J.D., Gaster, L.M., Reith, A.D., Laping, N.J., and Hill, C.S. (2002). SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol. Pharmacol. 62, 65–74.

    Article  CAS  PubMed  Google Scholar 

  • Isomaa, B., Almgren, P., Tuomi, T., Forsen, B., Lahti, K., Nissen, M., Taskinen, M.R., and Groop, L. (2001). Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24, 683–689.

    Article  CAS  PubMed  Google Scholar 

  • Kanematsu, A., Ramachandran, A., and Adam, R.M. (2007). GATA-6 mediates human bladder smooth muscle differentiation: involvement of a novel enhancer element in regulating alphasmooth muscle actin gene expression. Am. J. Physiol. Cell Physiol. 293, C1093–1102.

    Article  CAS  PubMed  Google Scholar 

  • Kanwar, Y.S., Wada, J., Sun, L., Xie, P., Wallner, E.I., Chen, S., Chugh, S., and Danesh, F.R. (2008). Diabetic nephropathy: mechanisms of renal disease progression. Exp. Biol. Med. 233, 4–11.

    Article  CAS  Google Scholar 

  • Keelan, P.C., Bielak, L.F., Ashai, K., Jamjoum, L.S., Denktas, A.E., Rumberger, J.A., Sheedy, I.P., Peyser, P.A., and Schwartz, R.S. (2001). Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation 104, 412–417.

    Article  CAS  PubMed  Google Scholar 

  • Konig, H.G., Kogel, D., Rami, A., and Prehn, J.H. (2005). TGF-ta1 activates two distinct type I receptors in neurons: implications for neuronal NF-{kappa}B signaling. J. Cell Biol. 168, 1077–1086.

    Google Scholar 

  • Korinek, V., Barker, N., Morin, P.J., van Wichen, D., de Weger, R., Kinzler, K.W., Vogelstein, B., and Clevers, H. (1997). Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma. Science 275, 1784–1787.

    Article  CAS  PubMed  Google Scholar 

  • Kottgen, A., Hwang, S.J., Rampersaud, E., Coresh, J., North, K.E., Pankow, J.S., Meigs, J.B., Florez, J.C., Parsa, A., Levy, D., et al. (2008). TCF7L2 variants associate with CKD progression and renal function in population-based cohorts. J. Am. Soc. Nephrol. 19, 1989–1999.

    Article  PubMed  Google Scholar 

  • Kou, I., Nakajima, M., and Ikegawa, S. (2007). Expression and regulation of the osteoarthritis-associated protein asporin. J. Biol. Chem. 282, 32193–32199.

    Article  CAS  PubMed  Google Scholar 

  • Liu, Z., and Habener, J.F. (2008). Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J. Biol. Chem. 283, 8723–8735.

    Article  CAS  PubMed  Google Scholar 

  • Luo, R.X., Postigo, A.A., and Dean, D.C. (1998). Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473.

    Article  CAS  PubMed  Google Scholar 

  • Lux, A., Attisano, L., and Marchuk, D.A. (1999). Assignment of transforming growth factor beta1 and beta3 and a third new ligand to the type I receptor ALK-1. J. Biol. Chem. 274, 9984–9992.

    Article  CAS  PubMed  Google Scholar 

  • Lyssenko, V., Lupi, R., Marchetti, P., Del Guerra, S., Orho-Melander, M., Almgren, P., Sjogren, M., Ling, C., Eriksson, K.F., Lethagen, A.L., et al. (2007). Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J. Clin. Invest. 117, 2155–2163.

    Article  CAS  PubMed  Google Scholar 

  • Matsubara, T., Abe, H., Arai, H., Nagai, K., Mima, A., Kanamori, H., Sumi, E., Takahashi, T., Matsuura, M., Iehara, N., et al. (2006). Expression of Smad1 is directly associated with mesangial matrix expansion in rat diabetic nephropathy. Lab. Invest. 86, 357–368.

    Article  CAS  PubMed  Google Scholar 

  • Mima, A., Arai, H., Matsubara, T., Abe, H., Nagai, K., Tamura, Y., Torikoshi, K., Araki, M., Kanamori, H., Takahashi, T., et al. (2008). Urinary Smad1 is a novel marker to predict later onset of mesangial matrix expansion in diabetic nephropathy. Diabetes 57, 1712–1722.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura, T., Fukui, M., Ebihara, I., Osada, S., Nagaoka, I., Tomino, Y., and Koide, H. (1993). mRNA expression of growth factors in glomeruli from diabetic rats. Diabetes 42, 450–456.

    Article  CAS  PubMed  Google Scholar 

  • Oh, S.P., Seki, T., Goss, K.A., Imamura, T., Yi, Y., Donahoe, P.K., Li, L., Miyazono, K., ten Dijke, P., Kim, S., et al. (2000). Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc. Natl. Acad. Sci. USA 97, 2626–2631.

    Article  CAS  PubMed  Google Scholar 

  • Park, I.S., Kiyomoto, H., Abboud, S.L., and Abboud, H.E. (1997). Expression of transforming growth factor-beta and type IV collagen in early streptozotocin-induced diabetes. Diabetes 46, 473–480.

    Article  CAS  PubMed  Google Scholar 

  • Parton, L.E., McMillen, P.J., Shen, Y., Docherty, E., Sharpe, E., Diraison, F., Briscoe, C.P., and Rutter, G.A. (2006). Limited role for SREBP-1c in defective glucose-induced insulin secretion from Zucker diabetic fatty rat islets: a functional and gene profiling analysis. Am. J. Physiol. Endocrinol. Metab. 291, E982–994.

    Article  CAS  PubMed  Google Scholar 

  • Sale, M.M., Smith, S.G., Mychaleckyj, J.C., Keene, K.L., Langefeld, C.D., Leak, T.S., Hicks, P.J., Bowden, D.W., Rich, S.S., and Freedman, B.I. (2007). Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy. Diabetes 56, 2638–2642.

    Article  CAS  PubMed  Google Scholar 

  • Sanai, T., Sobka, T., Johnson, T., el-Essawy, M., Muchaneta-Kubara, E.C., Ben Gharbia, O., el Oldroyd, S., and Nahas, A.M. (2000). Expression of cytoskeletal proteins during the course of experimental diabetic nephropathy. Diabetologia 43, 91–100.

    Article  CAS  PubMed  Google Scholar 

  • Schrijvers, B.F., De Vriese, A.S., and Flyvbjerg, A. (2004). From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines. Endocr. Rev. 25, 971–1010.

    Article  CAS  PubMed  Google Scholar 

  • Shimokawa, T., Furukawa, Y., Sakai, M., Li, M., Miwa, N., Lin, Y.M., and Nakamura, Y. (2003). Involvement of the FGF18 gene in colorectal carcinogenesis, as a novel downstream target of the beta-catenin/T-cell factor complex. Cancer Res. 63, 6116–6120.

    CAS  PubMed  Google Scholar 

  • Shu, L., Sauter, N.S., Schulthess, F.T., Matveyenko, A.V., Oberholzer, J., and Maedler, K. (2008). Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 57, 645–653.

    Article  CAS  PubMed  Google Scholar 

  • Sjogren, M., Lyssenko, V., Jonsson, A., Berglund, G., Nilsson, P., Groop, L., and Orho-Melander, M. (2008). The search for putative unifying genetic factors for components of the metabolic syndrome. Diabetologia 51, 2242–2251.

    Article  CAS  PubMed  Google Scholar 

  • Takamura, T., Kato, I., Kimura, N., Nakazawa, T., Yonekura, H., Takasawa, S., and Okamoto, H. (1998). Transgenic mice overexpressing type 2 nitric-oxide synthase in pancreatic beta cells develop insulin-dependent diabetes without insulitis. J. Biol. Chem. 273, 2493–2496.

    Article  CAS  PubMed  Google Scholar 

  • Tang, Y., Urs, S., and Liaw, L. (2008). Hairy-related transcription factors inhibit Notch-induced smooth muscle alpha-actin expression by interfering with Notch intracellular domain/CBF-1 complex interaction with the CBF-1-binding site. Circ. Res. 102, 661–668.

    Article  CAS  PubMed  Google Scholar 

  • Trembath, R.C., Thomson, J.R., Machado, R.D., Morgan, N.V., Atkinson, C., Winship, I., Simonneau, G., Galie, N., Loyd, J.E., Humbert, M., et al. (2001). Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N. Engl. J. Med. 345, 325–334.

    Article  CAS  PubMed  Google Scholar 

  • Urness, L.D., Sorensen, L.K., and Li, D.Y. (2000). Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat. Genet. 26, 328–331.

    Article  CAS  PubMed  Google Scholar 

  • Wang, S., and Hirschberg, R. (2009). Diabetes-relevant regulation of cultured blood outgrowth endothelial cells. Microvasc. Res. 78, 174–179.

    Article  PubMed  Google Scholar 

  • Warodomwichit, D., Arnett, D.K., Kabagambe, E.K., Tsai, M.Y., Hixson, J.E., Straka, R.J., Province, M., An, P., Lai, C.Q., Borecki, I., et al. (2009). Polyunsaturated fatty acids modulate the effect of TCF7L2 gene variants on postprandial lipemia. J. Nutr. 139, 439–446.

    Article  CAS  PubMed  Google Scholar 

  • Waterman, M.L. (2004). Lymphoid enhancer factor/T cell factor expression in colorectal cancer. Cancer Metastasis Rev. 23, 41–52.

    Article  CAS  PubMed  Google Scholar 

  • Weedon, M.N., Owen, K.R., Shields, B., Hitman, G., Walker, M., McCarthy, M.I., Hattersley, A.T., and Frayling, T.M. (2005). A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population. Diabetes 54, 2487–2491.

    Article  CAS  PubMed  Google Scholar 

  • Wiercinska, E., Wickert, L., Denecke, B., Said, H.M., Hamzavi, J., Gressner, A.M., Thorikay, M., ten Dijke, P., Mertens, P.R., Breitkopf, K., et al. (2006). Id1 is a critical mediator in TGF-betainduced transdifferentiation of rat hepatic stellate cells. Hepatology 43, 1032–1041.

    Article  CAS  PubMed  Google Scholar 

  • Yamagishi, S., Inagaki, Y., Okamoto, T., Amano, S., Koga, K., Takeuchi, M., and Makita, Z. (2002). Advanced glycation end product-induced apoptosis and overexpression of vascular endothelial growth factor and monocyte chemoattractant protein-1 in human-cultured mesangial cells. J. Biol. Chem. 277, 20309–20315.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto, Y., Kato, I., Doi, T., Yonekura, H., Ohashi, S., Takeuchi, M., Watanabe, T., Yamagishi, S., Sakurai, S., Takasawa, S., et al. (2001). Development and prevention of advanced diabetic nephropathy in RAGE-overexpressing mice. J. Clin. Invest. 108, 261–268.

    CAS  PubMed  Google Scholar 

  • Yao, Y., Zebboudj, A.F., Torres, A., Shao, E., and Bostrom, K. (2007). Activin-like kinase receptor 1 (ALK1) in atherosclerotic lesions and vascular mesenchymal cells. Cardiovasc. Res. 74, 279–289.

    Article  CAS  PubMed  Google Scholar 

  • Ziyadeh, F.N. (2004). Mediators of diabetic renal disease: the case for tgf-Beta as the major mediator. J. Am. Soc. Nephrol. 15, S55–S57.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Deapartment of Nephrology, Graduate School of Medicine, Institute of Health-Bio-Science, University of Tokushima, Tokushima, 770-8503, Japan

    Toshikazu Araoka, Hideharu Abe, Tatsuya Tominaga, Akira Mima, Taichi Murakami, Seiji Kishi, Kojiro Nagai & Toshio Doi

  2. Department of Nephrology, Graduate School of Medicine, University of Kyoto, Kyoto, 606-8501, Japan

    Takeshi Matsubara

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  1. Toshikazu Araoka
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  2. Hideharu Abe
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  3. Tatsuya Tominaga
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  4. Akira Mima
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  5. Takeshi Matsubara
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  6. Taichi Murakami
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  7. Seiji Kishi
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  8. Kojiro Nagai
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  9. Toshio Doi
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Correspondence to Hideharu Abe.

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Araoka, T., Abe, H., Tominaga, T. et al. Transcription factor 7-like 2 (TCF7L2) regulates activin receptor-like kinase 1 (ALK1)/Smad1 pathway for development of diabetic nephropathy. Mol Cells 30, 209–218 (2010). https://doi.org/10.1007/s10059-010-0109-9

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  • DOI: https://doi.org/10.1007/s10059-010-0109-9

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