Back
 IJCM  Vol.7 No.7 , July 2016
Macrophage TGF-β1 and the Proapoptotic Extracellular Matrix Protein BIGH3 Induce Renal Cell Apoptosis in Prediabetic and Diabetic Conditions
Abstract: Metabolically stressed kidney is in part characterized by infiltrating macrophages and macrophage-derived TGF-β1 that promote the synthesis of various ECM molecules. TGF-β1 strongly enhances the expression of the gene TGFBI that encodes a cell-adhesion class, proapoptotic ECM protein called BIGH3. We hypothesized that in a diabetic environment a relationship between infiltrating macrophages, macrophage-derived TGF-β1, and BIGH3 protein promotes renal cell death. To investigate this hypothesis, we used our mouse model of diabetic complications. Mice on a high-fat diet developed hypercholesterolemia, and exposure to streptozotocin rendered hypercholesterolemic mice diabetic. Immunohistochemical images show increased macrophage infiltration and BIGH3 protein in the kidney cortices of hypercholesterolemic and diabetic mice. Macrophages induced a two-fold increase in BIGH3 expression and an 86% increase in renal proximal tubule epithelial cell apoptosis. TGF-β1 antibody and TGF-β1 receptor chemical antagonist blocked macrophage-induced apoptosis. BIGH3 antibody completely blocked apoptosis that was induced by TGF-β1, and blocked apoptosis induced by exogenous recombinant BIGH3. These results uncover a distinctive interplay of macrophage-derived TGF-β1, BIGH3 protein, and apoptosis, and indicate that BIGH3 is central in a novel pathway that promotes diabetic nephropathy. Macrophage TGF-β1 and BIGH3 are identified as prediabetic biomarkers, and potential therapeutic targets for intervention in prediabetic and diabetic individuals.
Cite this paper: J. Moritz, R. , LeBaron, R. , Phelix, C. , Rupaimoole, R. , Seok Kim, H. , Tsin, A. and Asmis, R. (2016) Macrophage TGF-β1 and the Proapoptotic Extracellular Matrix Protein BIGH3 Induce Renal Cell Apoptosis in Prediabetic and Diabetic Conditions. International Journal of Clinical Medicine, 7, 496-510. doi: 10.4236/ijcm.2016.77055.
References

[1]   Chow, E.A., Henry, F., Gonzalez, V. and McIver, L. (2012) The Disparate Impact of Diabetes on Racial/Ethnic Minority Populations. Clinical Diabetes, 30, 130-133.
http://dx.doi.org/10.2337/diaclin.30.3.130

[2]   Kolset, S.O., Reinholt, F.P. and Jenssen, T. (2012) Diabetic Nephropathy and Extracellular Matrix. Journal of Histochemistry & Cytochemistry, 60, 976-986.
http://dx.doi.org/10.1369/0022155412465073

[3]   Yamamoto, T., Nakamura, T., Noble, N.A., Ruoslahti, E. and Border, W.A. (1993) Expression of Transforming Growth Factor Beta Is Elevated in Human and Experimental Diabetic Nephropathy. Proceedings of the National Academy of Sciences of the United States of America, 90, 1814-1818.
http://dx.doi.org/10.1073/pnas.90.5.1814

[4]   Ziyadeh, F.N. (1993) Renal Tubular Basement Membrane and Collagen Type IV in Diabetes Mellitus. Kidney International, 43, 114-120.
http://dx.doi.org/10.1038/ki.1993.19

[5]   Kim, J.E., Kim, S.J., Lee, B.H., Park, R.W., Kim, K.S. and Kim, I.S. (2000) Identification of Motifs for Cell Adhesion within the Repeated Domains of Transforming Growth Factor-Beta-Induced Gene, Betaig-h3. Journal of Biological Chemistry, 275, 30907-30915.
http://dx.doi.org/10.1074/jbc.M002752200

[6]   Skonier, J., Neubauer, M., Madisen, L., Bennett, K., Plowman, G.D. and Purchio, A.F. (1992) cDNA Cloning and Sequence Analysis of Beta ig-h3, a Novel Gene Induced in a Human Adenocarcinoma Cell Line after Treatment with Transforming Growth Factor-Beta. DNA & Cell Biology, 11, 511-522.
http://dx.doi.org/10.1089/dna.1992.11.511

[7]   Andersen, R.B., Karring, H., Moller-Pedersen, T., Valnickova, Z., Thogersen, I.B., Hedegaard, C.J., Kristensen, T., Klintworth, G.K. and Enghild, J.J. (2004) Purification and Structural Characterization of Transforming Growth Factor Beta Induced Protein (TGFBIp) from Porcine and Human Corneas. Biochemistry, 43, 16374-16384.
http://dx.doi.org/10.1021/bi048589s

[8]   Kim, J.E., Kim, S.J., Jeong, H.W., Lee, B.H., Choi, J.Y., Park, R.W., Park, J.Y. and Kim, I.S. (2003) RGD Peptides Released from Beta ig-h3, a TGF-Beta-Induced Cell-Adhesive Molecule, Mediate Apoptosis. Oncogene, 22, 2045-2053.
http://dx.doi.org/10.1038/sj.onc.1206269

[9]   Zamilpa, R., Rupaimoole, R., Phelix, C.F., Somaraki-Cormier, M., Haskins, W., Asmis, R. and LeBaron, R.G. (2009) C-Terminal Fragment of Transforming Growth Factor Beta-Induced Protein (TGFBIp) Is Required for Apoptosis in Human Osteosarcoma Cells. Matrix Biology, 28, 347-353.
http://dx.doi.org/10.1016/j.matbio.2009.05.004

[10]   Han, J.H., Ha, S.W., Lee, I.K., Kim, B.W. and Kim, J.G. (2010) High Glucose-Induced Apoptosis in Bovine Retinal Pericytes Is Associated with Transforming Growth Factor Beta and betaIG-H3: betaIG-H3 Induces Apoptosis in Retinal Pericytes by Releasing Arg-Gly-Asp Peptides. Clin Exp Ophthalmol, 38, 620-628.
http://dx.doi.org/10.1111/j.1442-9071.2010.02276.x

[11]   Mondragon, A.A., Betts-Obregon, B.S., Moritz, R.J., Parvathaneni, K., Navarro, M.M., Kim, H.S., Lee, C.F., LeBaron, R.G., Asmis, R. and Tsin, A.T. (2015) BIGH3 Protein and Macrophages in Retinal Endothelial Cell Apoptosis. Apoptosis, 20, 29-37.
http://dx.doi.org/10.1007/s10495-014-1052-6

[12]   Morand, S., Buchillier, V., Maurer, F., Bonny, C., Arsenijevic, Y., Munier, F.L. and Schorderet, D.F. (2003) Induction of Apoptosis in Human Corneal and HeLa Cells by Mutated BIGH3. In-vestigative Ophthalmology & Visual Science, 44, 2973-2979.
http://dx.doi.org/10.1167/iovs.02-0661

[13]   Chow, F., Ozols, E., Nikolic-Paterson, D.J., Atkins, R.C. and Tesch, G.H. (2004) Macrophages in Mouse Type 2 Diabetic Nephropathy: Correlation with Diabetic State and Progressive Renal Injury. Kidney International, 65, 116-128.
http://dx.doi.org/10.1111/j.1523-1755.2004.00367.x

[14]   Ricardo, S.D., van Goor, H. and Eddy, A.A. (2008) Macro-phage Diversity in Renal Injury and Repair. Journal of Clinical Investigation, 118, 3522-3530.
http://dx.doi.org/10.1172/JCI36150

[15]   Lange-Sperandio, B., Cachat, F., Thornhill, B.A. and Chevalier, R.L. (2002) Selectins Mediate Macrophage Infiltration in Obstructive Nephropathy in Newborn Mice. Kidney International, 61, 516-524.
http://dx.doi.org/10.1046/j.1523-1755.2002.00162.x

[16]   Tesch, G.H., Schwarting, A., Kinoshita, K., Lan, H.Y., Rollins, B.J. and Kelley, V.R. (1999) Monocyte Chemoattractant Protein-1 Promotes Macrophage-Mediated Tubular Injury, but Not Glomerular Injury, in Nephrotoxic Serum Nephritis. Journal of Clinical Investigation, 103, 73-80.
http://dx.doi.org/10.1172/JCI4876

[17]   Chow, F.Y., Nikolic-Paterson, D.J., Ozols, E., Atkins, R.C., Rollin, B.J. and Tesch, G.H. (2006) Monocyte Chemoattractant Protein-1 Promotes the Development of Diabetic Renal Injury in Streptozotocin-Treated Mice. Kidney International, 69, 73-80.
http://dx.doi.org/10.1038/sj.ki.5000014

[18]   Kipari, T., Cailhier, J.F., Ferenbach, D., Watson, S., Houlberg, K., Walbaum, D., Clay, S., Savill, J. and Hughes, J. (2006) Nitric Oxide Is an Important Mediator of Renal Tubular Epithelial Cell Death in Vitro and in Murine Experimental Hydronephrosis. American Journal of Pathology, 169, 388-399.
http://dx.doi.org/10.2353/ajpath.2006.050964

[19]   McDonald, P.P., Fadok, V.A., Bratton, D. and Henson, P.M. (1999) Transcriptional and Translational Regulation of Inflammatory Mediator Production by Endogenous TGF-Beta in Macrophages That Have Ingested Apoptotic Cells. The Journal of Immunology, 163, 6164-6172.

[20]   Wynn, T.A. and Barron, L. (2010) Macrophages: Master Regulators of Inflammation and Fibrosis. Seminars in Liver Disease, 30, 245-257.
http://dx.doi.org/10.1055/s-0030-1255354

[21]   Sharma, K., Ziyadeh, F.N., Alzahabi, B., McGowan, T.A., Kapoor, S., Kurnik, B.R., Kurnik, P.B. and Weisberg, L.S. (1997) Increased Renal Production of Transforming Growth Factor-Beta1 in Patients with Type II Diabetes. Diabetes, 46, 854-859.
http://dx.doi.org/10.2337/diab.46.5.854

[22]   Gilbert, R.E., Wilkinson-Berka, J.L., Johnson, D.W., Cox, A., Soulis, T., Wu, L.L., Kelly, D.J., Jerums, G., Pollock, C.A. and Cooper, M.E. (1998) Renal Expression of Transforming Growth Factor-Beta Inducible Gene-h3 (Betaig-h3) in Normal and Diabetic Rats. Kidney International, 54, 1052-1062.
http://dx.doi.org/10.1046/j.1523-1755.1998.00081.x

[23]   Lee, S.H., Bae, J.S., Park, S.H., Lee, B.H., Park, R.W., Choi, J.Y., Park, J.Y., Ha, S.W., Kim, Y.L., Kwon, T.H. and Kim, I.S. (2003) Expression of TGF-Beta-Induced Matrix Protein Betaig-h3 Is Up-Regulated in the Diabetic Rat Kidney and Human Proximal Tubular Epithelial Cells Treated with High Glucose. Kidney International, 64, 1012-1021.
http://dx.doi.org/10.1046/j.1523-1755.2003.00158.x

[24]   Qiao, M., Zhao, Q., Lee, C.F., Tannock, L.R., Smart, E.J., LeBaron, R.G., Phelix, C.F., Rangel, Y. and Asmis, R. (2009) Thiol Oxidative Stress Induced by Metabolic Disorders Amplifies Macrophage Chemotactic Responses and Accelerates Atherogenesis and Kidney Injury in LDL Receptor-Deficient Mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 29, 1779-1786.
http://dx.doi.org/10.1161/ATVBAHA.109.191759

[25]   Ullevig, S.L., Zhao, Q., Zamora, D. and Asmis, R. (2011) Ursolic Acid Protects Diabetic Mice against Monocyte Dysfunction and Accelerated Atherosclerosis. Atherosclerosis, 219, 409-416.
http://dx.doi.org/10.1016/j.atherosclerosis.2011.06.013

[26]   Wintergerst, E.S., Jelk, J. and Asmis, R. (1998) Differential Expression of CD14, CD36 and the LDL Receptor on Human Monocyte-Derived Macrophages. A Novel Cell Culture System to Study Macrophage Differentiation and Heterogeneity. Histochemistry and Cell Biology, 110, 231-241.
http://dx.doi.org/10.1007/s004180050285

[27]   Ferguson, J.W., Thoma, B.S., Mikesh, M.F., Kramer, R.H., Bennett, K.L., Purchio, A., Bellard, B.J. and LeBaron, R.G. (2003) The Extracellular Matrix Protein Betaig-h3 Is Expressed at Myotendinous Junctions Andsupports Muscle Cell Adhesion. Cell and Tissue Research, 313, 93-105.
http://dx.doi.org/10.1007/s00441-003-0743-z

[28]   Ding, G., van Goor, H., Frye, J. and Diamond, J.R. (1994) Transforming Growth Factor-Beta Expression in Macrophages during Hypercholesterolemic States. American Journal of Physiology, 267, F937-F943.

[29]   Eddy, A.A. (1996) Interstitial Inflammation and Fibrosis in Rats with Diet-Induced Hypercholesterolemia. Kidney International, 50, 1139-1149.
http://dx.doi.org/10.1038/ki.1996.421

[30]   Lee, S.H., Kim, E.J., Suk, K., Kim, I.S. and Lee, W.H. (2010) TL1A Induces the Expression of TGF-Beta-Inducible Gene h3 (Betaig-h3) through PKC, PI3K, and ERK in THP-1 Cells. Cellular Immunology, 266, 61-66.
http://dx.doi.org/10.1016/j.cellimm.2010.08.013

[31]   Ween, M.P., Lokman, N.A., Hoffmann, P., Rodgers, R.J., Ricciardelli, C. and Oehler, M.K. (2011) Transforming Growth Factor-Beta-Induced Protein Secreted by Peritoneal Cells Increases the Metastatic Potential of Ovarian Cancer Cells. International Journal of Cancer, 128, 1570-1584.
http://dx.doi.org/10.1002/ijc.25494

[32]   Aihara, K., Ikeda, Y., Yagi, S., Akaike, M. and Matsumoto, T. (2010) Transforming Growth Factor-Beta1 as a Common Target Molecule for Development of Cardiovascular Diseases, Renal Insufficiency and Metabolic Syndrome. Cardiology Research and Practice, 2011, Article ID: 175381.

[33]   Park, S.W., Bae, J.S., Kim, K.S., Park, S.H., Lee, B.H., Choi, J.Y., Park, J.Y., Ha, S.W., Kim, Y.L., Kwon, T.H., Kim, I.S. and Park, R.W. (2004) Beta ig-h3 Promotes Renal Proximal Tubular Epithelial Cell Adhesion, Migration and Proliferation through the Interaction with Alpha3Beta1 Integrin. Experimental and Molecular Medicine, 36, 211-219.
http://dx.doi.org/10.1038/emm.2004.29

[34]   Cha, D.R., Kim, I.S., Kang, Y.S., Han, S.Y., Han, K.H., Shin, C., Ji, Y.H. and Kim, N.H. (2005) Urinary Concentration of Transforming Growth Factor-Beta-Inducible Gene-h3 (Betaig-h3) in Patients with Type 2 Diabetes Mellitus. Diabetic Medicine, 22, 14-20.
http://dx.doi.org/10.1111/j.1464-5491.2004.01295.x

[35]   Ha, S.W., Kim, H.J., Bae, J.S., Jeong, G.H., Chung, S.C., Kim, J.G., Park, S.H., Kim, Y.L., Kam, S., Kim, I.S. and Kim, B.W. (2004) Elevation of Urinary Betaig-h3, Transforming Growth Factor-Beta-Induced Protein in Patients with Type 2 Diabetes and Nephropathy. Diabetes Research and Clinical Practice, 65, 167-173.
http://dx.doi.org/10.1016/j.diabres.2004.01.007

[36]   Riojas, M.A., Villanueva-Vedia, R.E., Zamilpa, R., Chen, X., Du, L.C., Phelix, C.F. and LeBaron, R.G. (2008) Prevalence of Diabetes Mellitus and Correlation of Urinary Transforming Growth Factor-Beta1 with Blood Hemoglobin A1C in the Atascosa Diabetes Study. Ethnicity & Disease, 18, 54-59.

[37]   Han, B., Luo, H., Raelson, J., Huang, J., Li, Y., Tremblay, J., Hu, B., Qi, S. and Wu, J. (2014) TGFBI (Betaig-h3) Is a Diabetes-Risk Gene Based on Mouse and Human Genetic Studies. Human Molecular Genetics, 23, 4597-4611.
http://dx.doi.org/10.1093/hmg/ddu173

[38]   Garud, M.S. and Kulkarni, Y.A. (2014) Hyperglycemia to Nephropathy via Transforming Growth Factor Beta. Current Diabetes Reviews, 10, 182-189.
http://dx.doi.org/10.2174/1573399810666140606103645

[39]   Skonier, J., Bennett, K., Rothwell, V., Kosowski, S., Plowman, G., Wallace, P., Edelhoff, S., Disteche, C., Neubauer, M., Marquardt, H., et al. (1994) Betaig-h3: A Transforming Growth Factor-Beta-Responsive Gene Encoding a Secreted Protein That Inhibits Cell Attachment in Vitro and Suppresses the Growth of CHO Cells in Nude Mice. DNA and Cell Biology, 13, 571-584.
http://dx.doi.org/10.1089/dna.1994.13.571

[40]   Karring, H., Runager, K., Thogersen, I.B., Klintworth, G.K., Hojrup, P. and Enghild, J.J. (2012) Composition and Proteolytic Processing of Corneal Deposits Associated with Mutations in the TGFBI Gene. Experimental Eye Research, 96, 163-170.
http://dx.doi.org/10.1016/j.exer.2011.11.014

[41]   Kim, Y.H., Kwon, H.J. and Kim, D.S. (2012) Matrix Metalloproteinase 9 (MMP-9)-Dependent Processing of Betaig-h3 (betaig-h3) Regulates Cell Migration, Invasion, and Adhesion. The Journal of Biological Chemistry, 46, 38957-38969.
http://dx.doi.org/10.1074/jbc.M112.357863

[42]   Nacu, N., Luzina, I.G., Highsmith, K., Lockatell, V., Pochetuhen, K., Cooper, Z.A., Gillmeister, M.P., Todd, N.W. and Atamas, S.P. (2008) Macrophages Produce TGF-Beta-Induced (Beta-ig-h3) Following Ingestion of Apoptotic Cells and Regulate MMP14 Levels and Collagen Turnover in Fibroblasts. The Journal of Immunology, 180, 5036-5044.
http://dx.doi.org/10.4049/jimmunol.180.7.5036

[43]   Brennan, E.P., Morine, M.J., Walsh, D.W., Roxburgh, S.A., Lindenmeyer, M.T., Brazil, D.P., Gaora, P.O., Roche, H.M., Sadlier, D.M., Cohen, C.D., Consortium, G., Godson, C. and Martin, F. (2012) Next-Generation Sequencing Identifies TGF-Beta1-Associated Gene Expression Profiles in Renal Epithelial Cells Reiterated in Human Diabetic Nephropathy. Biochimica et Biophysica Acta, 1822, 589-599.
http://dx.doi.org/10.1016/j.bbadis.2012.01.008

[44]   Ma, C., Rong, Y., Radiloff, D.R., Datto, M.B., Centeno, B., Bao, S., Cheng, A.W., Lin, F., Jiang, S., Yeatman, T.J. and Wang, X.F. (2008) Extracellular Matrix Protein Betaig-h3/TGFBI Promotes Metastasis of Colon Cancer by Enhancing Cell Extravasation. Genes & Development, 22, 308-321.
http://dx.doi.org/10.1101/gad.1632008

[45]   Fan, J.M., Ng, Y.Y., Hill, P.A., Nikolic-Paterson, D.J., Mu, W., Atkins, R.C. and Lan, H.Y. (1999) Transforming Growth Factor-Beta Regulates Tubular Epithelial-Myofibroblast Transdifferentiation in Vitro. Kidney International, 56, 1455-1467.
http://dx.doi.org/10.1046/j.1523-1755.1999.00656.x

[46]   Yang, J. and Liu, Y. (2002) Blockage of Tubular Epithelial to Myofibroblast Transition by Hepatocyte Growth Factor Prevents Renal Interstitial Fibrosis. Journal of the American Society of Nephrology, 13, 96-107.

[47]   Kim, H.J. and Kim, I.S. (2008) Transforming Growth Factor-Beta-Induced Gene Product, as a Novel Ligand of Integrin AlphamBeta2, Promotes Monocyte Adhesion, Migration and Chemotaxis. The International Journal of Biochemistry & Cell Biology, 40, 991-1004.
http://dx.doi.org/10.1016/j.biocel.2007.11.001

[48]   Kim, J.E., Jeong, H.W., Nam, J.O., Lee, B.H., Choi, J.Y., Park, R.W., Park, J.Y. and Kim, I.S. (2002) Identification of Motifs in the Fasciclin Domains of the Transforming Growth Factor-Beta-Induced Matrix Protein Betaig-h3 That Interact with the Alpha vBeta5 Integrin. The Journal of Biological Chemistry, 277, 46159-46165.
http://dx.doi.org/10.1074/jbc.M207055200

[49]   Lee, B.H., Bae, J.S., Park, R.W., Kim, J.E., Park, J.Y. and Kim, I.S. (2006) Betaig-h3 Triggers Signaling Pathways Mediating Adhesion and Migration of Vascular Smooth Muscle Cells through AlphavBeta5 Integrin. Experimental & Molecular Medicine, 38, 153-161.
http://dx.doi.org/10.1038/emm.2006.19

 
 
Top