Nanosized titanium dioxide resulted in the activation of TGF-β/Smads/p38MAPK pathway in renal inflammation and fibration of mice
Corresponding Author
F Hong
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Correspondence to: F. Hong; e-mail: [email protected]Search for more papers by this authorN Wu
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Search for more papers by this authorY Ge
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Search for more papers by this authorY Zhou
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Search for more papers by this authorT Shen
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorQ Qiang
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorQ Zhang
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorM Chen
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorY Wang
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorJ Hong
Medical College of Soochow University, Suzhou, 215123 China
Search for more papers by this authorCorresponding Author
F Hong
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Correspondence to: F. Hong; e-mail: [email protected]Search for more papers by this authorN Wu
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Search for more papers by this authorY Ge
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Search for more papers by this authorY Zhou
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
These authors contributed equally to this work.
Search for more papers by this authorT Shen
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorQ Qiang
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorQ Zhang
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorM Chen
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorY Wang
Jiangsu Collaborative Innovation Center of Regional Modern Agriculture & Environmental Protection, Huaiyin Normal University, Huaian, 223300 China
Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, Huaiyin Normal University, Huaian, 223300 China
School of Life Sciences, Huaiyin Normal University, Huaian, 223300 China
Search for more papers by this authorJ Hong
Medical College of Soochow University, Suzhou, 215123 China
Search for more papers by this authorAbstract
Titanium dioxide nanoparticles (TiO2 NPs) have been demonstrated to damage the kidneys. However, whether chronic nephritis leads to renal fibration or the fibrosis is associated with the activation of TGF-β/Smads/p38MAPK pathway caused by TiO2 NPs exposure is not well understood. Forty male mice were separately exposed to 0, 2.5, 5, or 10 mg/kg body weight TiO2 NPs for 6 months. Renal biochemical functions and levels of TGF-β/Smads/p38MAPK pathway-related markers and extracellular matrix (ECM) expression in the kidneys were investigated. The findings showed that subchronic TiO2 NPs exposure increased levels of urinary creatisix (Cr), N-acetyl-glucosaminidase, and vanin-1, resulted in severe renal inflammation and fibration. Furthermore, TiO2 NP exposure upregulated expression of transforming growth factor-β1 (TGF-β1, 0.07- to 2.72-fold), Smad2 (0.42- to 1.63-fold), Smad3 (0.02- to 1.94-fold), ECM (0.15- to 2.75-fold), α-smooth muscle actin (0.14- to 3.06-fold), p38 mitogen-activated protein kinase (p38MAPK, 0.11- to 3.78-fold), and nuclear factor-κB (0.4- to 2.27-fold), and downregulated Smad7 (0.05- to 0.61-fold) expression in mouse kidney. Subchronic TiO2 NPs exposure induced changes of renal characteristics towards inflammation and fibration may be mediated via TGF-β/Smads/p38MAPK pathway, and the uses of TiO2 NPs should be carried out cautiously, especially in humans. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1452–1461, 2016.
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REFERENCES
- 1Nel A, Xia T, Madler L, Li N. Toxic potential of materials at the nanolevel. Science 2006; 311: 622–627.
- 2Habibi MH, Esfahani MN, Egerton TA. Photochemical characterization and photocatalytic properties of a nanostructure composite TiO2 film. Int J Photoenergy 2007; 2007: 13653–13661.
- 3Sen G, Wu ZB, Zhao WR. TiO2-based building materials: Above and beyond traditional applications. Chin Sci Bull 2009; 54: 1137–1142.
- 4 EPA. External Review Draft, Nanomaterial Case Studies: Nanoscale Titanium Dioxide in Water Treatment and in Topical Sunscreen. United States Environmental Protection Agency. 2009. Available at: http://www.safenano.org/SingleNews.aspx? NewsId¼788. Last accessed on October 9, 2010.
- 5Wang JX, Zhou GQ, Chen CY, Yu HW, Wang TC, Ma YM, Jia G, Gao YX, Li B, Sun J, Li YF, Jia F, Zhao YL, Z.F. Chai YL. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 2007, 168: 176–185.
- 6 IARC. Carbon Black, Titanium Dioxide and Talc. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 93. Lyon: International Agency for Research on Cancer; 2006.
- 7Li SQ, Zhu R, Zhu H, Xue M, Sun XY, Yao SD, Wang SL. Nanotoxicity of TiO2 nanoparticles to erythrocyte in vitro. Food Chem Toxicol 2008; 46: 3626–3631.
- 8Navarro E, Baun A, Behra R, Hartmann NB, Filser J, Miao AJ, Quigg A, Santschi PH, Sigg L. Environmental behavior and ecotoxicity of engineered nanoparticles to algae, plants, and fungi. Ecotoxicol 2008; 17: 372–386.
- 9Huang KT, Wu CT, Huang KH, Lin WC, Chen CM, Guan SS, Chiang CK, Liu SH. Titanium nanoparticle inhalation induces renal fibrosis in mice via an oxidative stress upregulated transforming growth factor-β pathway. Chem Res Toxicol 2015; 28: 354–364.
- 10Scown TM, van Aerle RY, Johnston BD, Cumberland S, Lead JR, Richard O, Tyler CR. High doses of intravenously administered titanium dioxide nanoparticles accumulate in the kidneys of rainbow trout but with no observable impairment of renal function. Toxicol Sci 2009; 109: 372–380.
- 11Liu HT, Ma LL, Zhao JF, Liu J, Yan JY, Ruan J, Hong FS. Biochemical toxicity of mice caused by nano-anatase TiO2 particles. Biol Trace Elem Res 2009; 129: 170–180.
- 12Zhao JF, Wang J, Wang SS, Zhao XY, Yan JY, Ruan J, Li N, Duan YM, Wang H, Hong FS. The mechanism of oxidative damage in nephrotoxicity of mice caused by nano-anatase TiO2. J Exp Nanosci 2010; 5: 447–462.
- 13Chen JY, Dong X, Zhao J, Tang GP. In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitoneal injection. J Appl Toxicol 2009; 29: 330–337.
- 14Gui SX, Zhang ZL, Zheng L, Sun QQ, Sang XZ, Liu XR, Gao GD, Cui YL, Cheng Z, Cheng J, Tang M, Hong FS. The molecular mechanism of kidney injury of mice caused by exposure to titanium dioxide nanoparticles. J Hazard Mater 2011; 195: 365–370.
- 15Gui SX, Li BY, Zhao XY, Sheng L, Hong J, Yu XH, Sang XZ, Sun QQ, Ze YG, Wang L, Hong FS. Renal injury and Nrf2 modulation in mouse kidney following exposure to titanium dioxide nanoparticles. J Agric Food Chem 2013; 61: 8959–8968.
- 16Hong FS, Hong J, Wang L, Zhou YJ, Liu D, Xu BQ, Yu XH, Sheng L. Chronic exposure to nanoparticulate TiO2 causes renal fibrosis involving activation of the Wnt pathway in mouse kidney. J. Agric. Food Chem 2015; 63: 1639–1647.
- 17Franklin TJ. Therapeutic approaches to organ fibrosis. Int J Biochem Cell Biol 1997; 29: 79–89.
- 18Eddy AA, Neilson EG. Chronic kidney disease progression. J Am Soc Nephrol 2006; 17: 2964–2966.
- 19Lee SB, Kalluri R. Mechanistic connection between inflammation and fibrosis. Kidney Int 2010; 78: S22–S26.
- 20Ueha S, Shand FHW, Matsushima K. Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis. Front Immunol 2012; 3: 71.
- 21Humphreys BD, Xu FF, Sabbisetti V, Grgic I, Naini SM, Wang NN, Chen GC, Xiao S, Patel D, Henderson JM, Ichimura T, Mou S, Soeung S, McMahon AP, Kuchroo VK, Bonventre JV. Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis. J Clin Invest 2013; 123: 4023–4035.
- 22Lan HY. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation. Int J Biol Sci 2011; 7: 1056–1067.
- 23Lan HY, Chung CK. TGF-β/Smad signaling in kidney disease. Semin Nephrol 2012; 32: 236–243.
- 24Sugiyama N, Kohno M, Yokoyama T. Inhibition of the p38 MAPK pathway ameliorates renal fibrosis in an NPHP2 mouse model. Nephrol Dial Transplant 2012; 27: 1351–1358.
- 25Bottinger EP. TGF-beta in renal injury and disease. Semin Nephrol 2007; 27: 309–320.
- 26Wang W, Koka V, Lan HY. Transforming growth factor-beta and Smad signalling in kidney diseases. Nephrol (Carlton) 2005; 10: 48–56.
- 27Yang P, Lu C, Hua N, Du Y. Titanium dioxide nanoparticles co-doped with Fe3+ and Eu3+ ions for photocatalysis. Mater Lett 2002; 57: 794–801.
- 28Hu RP, Zheng L, Zhang T, Cui YL, Gao GD, Cheng Z, Chen J, Tang M, Hong FS. Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 2011; 191: 32–40.
- 29Outlines Guidance on Handling Titanium Dioxide (TiO2). Atlanta: National Institute for Occupational Safety and Health; 2011.
- 30Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Cogliano V. Carcinogenicity of carbon black, titanium dioxide, and talc. Lancet Oncol 2006; 7: 295–296.
- 31Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 2009; 55: 611–622.
- 32Schefe JH, Lehmann KE, Buschmann IR, Unger T, Funke-Kaiser H. Quantitative real-time RT-PCR data analysis: Current concepts and the novel “gene expression's CT difference” formula. J Mol Med 2006; 84: 901–910.
- 33Benani A, Troy S, Carmona MC, Fioramonti X, Lorsignol A, Leloup C, Casteilla L, Pénicaud L. Role for mitochondrial reactive oxygen species in brain lipid sensing: Redox regulation of food intake. Diabetes 2007; 56: 152–160.
- 34Hosohata K, Ando H, Fujiwara Y, Fujimura A. Vanin-1; a potential biomarker for nephrotoxicant-induced renal injury. Toxicology 2011; 290: 82–88.
- 35Martin F, Penet MF, Malergue F, Lepidi H, Dessein A, Galland F, de Reggi M, Naquet P, Gharib B. Vanin-1(−/−) mice show decreased NSAID- and schistosoma-induced intestinal inflammation associated with higher glutathione stores. J Clin Invest 2004; 113: 591–597.
- 36Chen Z, Meng H, Xing GM, Chen CY, Zhao YL, Jia G, Wang TC, Yuan H, Ye C, Zhao F, Chai ZF, Zhu CF, Fang XH, Ma BC, Wan LJ. Acute toxicological effects of copper nanoparticles in vivo. Toxicol Lett 2006; 163: 109–120.
- 37Meng H, Chen Z, Xing G, Yuan H, Chen C. Ultrahigh reactivity provokes nanotoxicity: Explanation of oral toxicity of nanocopper particles. Toxicol Lett 2007; 175: 102–110.
- 38Sarkar A, Das J, Manna P, Sil PC. Nano-copper induces oxidative stress and apoptosis in kidney via both extrinsic and intrinsic pathways. Toxicology 2011; 290: 208–217.
- 39Wang B, Feng WY, Wang TC, Jia G, Wang M, Shi JW, Zhang F, Zhao YL, Chai ZF. Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice. Toxicol Lett 2016; 161: 115–123.
- 40Yan GY, Huang YN, Bu Q, Lv L, Deng PC, Zhou JQ, Wang YL, Yang YZ, Liu QQ, Cen XB, Zhao YL. Zinc oxide nanoparticles cause nephrotoxicity and kidney metabolism alterations in rats. J Environ Sci Health Part A 2012; 4: 577–588.
- 41Liu SC, Xu LJ, Zhang T, Ren GG, Yang Z. Oxidative stress and apoptosis induced by nanosized titanium dioxide in PC12 cells. Toxicology 2010; 267: 172–177.
- 42Wu J, Sun J, Xue Y. Involvement of JNK and P53 activation in G2/M cell cycle arrest and apoptosis induced by titanium dioxide nanoparticles in neuron cells. Toxicol Lett 2010; 199: 269–276.
- 43Sayes CM, Wahi R, Kurian PA, Liu Y, West JL, Ausman KD, Warheit DB, Colvin VL. Correlating nanoscale titania structure with toxicity: A cytotoxicity and inflammatory response study with human dermal fibroblasts and human lung epithelial cells. Toxicol Sci 2006; 92: 174–185.
- 44Sabokbar A, Pandey R, Athanasou NA. The effect of particle size and electrical charge on macrophage-osteoclast differentiation and bone resorption. J Mater Sci Mater Med 2003; 14: 731–738.
- 45Long TC, Saleh N, Tilton RD, Lowry G, Veronesi B. Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): Implications for nanoparticle neurotoxicity. Environ Sci Technol 2006; 40: 4346–4352.
- 46Long TC, Tajuba J, Sama P, Saleh N, Swartz C, Parker J, Hester S, Lowry GV, Veronesi B. Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro. Environ Health Perspect 2007; 115: 1631–1637.
- 47Nel A, Madler L, Velegol D, Xia TMV, Hoek E, Somasundaran P, Klaessig F, Castranova V, Thompson M. Understanding biophysicochemical interactions at nano-bio interface. Nat Mater 2009; 8: 543–556.
- 48Domingos R, Baaloush M, Yonju-Nam M, Reid M, Tufenkji N, Lead J, Leppard G, Wilkinson K. Characterizing manufactured nanoparticles in the environment: Multimethod determinationof particle sizes. Environ Sci Technol 2009; 43: 7277–7284.
- 49Gentile F, Ferrari M, Decuzzi P. The transport of nanoparticles in blood vessels: The effect of vessel permeability and blood rheology. Ann Biomed Eng 2008; 36: 254–261.
- 50Lan HY. Tubular epithelial-myofibroblast transdifferentiation mechanisms in proximal tubule cells. Curr Opin Nephrol Hypertens 2003; 12: 25–29.
- 51Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS. Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest 1996; 74: 991–1003.
- 52Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L, Roberts AB, Sporn MB, Thorgeirsson SS. Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci USA 1995; 92: 2572–2576.
- 53Lan HY, Chung AC. Transforming growth factor-β and Smads. Contrib Nephrol 2011; 170: 75–82.
- 54Li JH, Huang XR, Zhu HJ, Oldfield M, Cooper M, Truong LD, Johnson RJ, Lan HY. Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. FASEB J 2004; 18: 176–178.
- 55Chung AC, Zhang H, Kong YZ, Tan JJ, Huang XR, Kopp JB, Lan HY. Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling. J Am Soc Nephrol 2010; 21: 249–260.
- 56Wang W, Huang XR, Canlas E, Oka K, Truong LD, Deng C, Bhowmick NA, Ju W, Bottinger EP, Lan HY. Essential role of Smad3 in angiotensin II-induced vascular fibrosis. Circ Res 2006; 98: 1032–1039.
- 57Yang F, Chung AC, Huang XR, Lan HY. Angiotensin II induces connective tissue growth factor and collagen I expression via transforming growth factor-beta-dependent and -independent Smad pathways: the role of Smad3. Hypertension 2009; 54: 877–884.
- 58Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 2000; 6: 1365–1375.
- 59Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T, Miyazono K. Smurf1 interacts with transforming growth factor-beta type I receptor through Smad7 and induces receptor degradation. J Biol Chem 2001; 276: 12477–12480.
- 60Liu FY, Li XZ, Peng YM, Liu H, Liu YH. Arkadia regulates TGFβ signaling during renal tubular epithelial to mesenchymal cell transition. Kidney Int 2008; 73: 588–594.
- 61Fukasawa H, Yamamoto T, Togawa A, Ohashi N, Fujigaki Y, Oda T, Uchida C, Kitagawa K, Hattori T, Suzuki S, Kitagawa M, Hishida A. Down-regulation of Smad7 expression by ubiquitin-dependent degradation contributes to renal fibrosis in obstructive nephropathy in mice. Proc Natl Acad Sci USA 2004; 101: 8687–8692.
- 62Inoue Y, Imamura T. Regulation of TGF-beta family signaling by E3 ubiquitin ligases. Cancer Sci 2008; 99: 2107–2112.
- 63Wang W, Huang XR, Li AG, Liu F, Li JH, Truong LD, Wang XJ, Lan HY. Signaling mechanism of TGF-beta1 in prevention of renal inflammation: role of Smad7. J Am Soc Nephrol 2005; 16: 1371–1383.
- 64Chen H, Huang XR, Wang W, Li J, Heuchel RL, Chung AC, Lan HY. The protective role of Smad7 in diabetic kidney disease: Mechanism and therapeutic potential. Diabetes 2010; 60: 590–601.
- 65Chung AC, Huang XR, Zhou L, Heuchel R, Lai KN, Lan HY. Disruption of the Smad7 gene promotes renal fibrosis and inflammation in unilateral ureteral obstruction (UUO) in mice. Nephrol Dial Transplant 2009; 24: 1443–1454.
- 66Ka SM, Huang XR, Lan HY, Tsai PY, Yang SM, Shui HA, Chen A. Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice. J Am Soc Nephrol 2007; 18: 1777–1788.
- 67Ng YY, Hou CC, Wang W, Huang XR, Lan HY. Blockade of NFkappaB activation and renal inflammation by ultrasound-mediated gene transfer of Smad7 in rat remnant kidney. Kidney Int 2005; 94: S83–S91.
- 68Yang F, Huang XR, Chung AC, Hou CC, Lai KN, Lan HY. Essential role for Smad3 in angiotensin II-induced tubular epithelial-mesenchymal transition. J Pathol 2010; 221: 390–401.
- 69Zhou L, Fu P, Huang XR, Liu F, Chung AC, Lai KN, Lan HY. Mechanism of chronic aristolochic acid nephropathy: role of Smad3. Am J Physiol Renal Physiol 2010; 298: F1006–F1017.
- 70Zhou Y, Mao H, Li S, Cao S, Li Z, Zhuang S, Fan J, Dong X, Borkan SC, Wang Y, Yu X. HSP72 inhibits Smad3 activation and nuclear translocation in renal epithelial-to-mesenchymal transition. J Am Soc Nephrol 2010; 21: 598–609.
- 71Ng YY, Chen YM, Tsai TJ, Lan XR, Yang WC, Lan HY. Pentoxifylline inhibits transforming growth factor-β signaling and renal fibrosis in experimental crescentic glomerulonephritis in rats. Am J Nephrol 2009; 29: 43–53.
- 72Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 2001; 276: 17058–17062.
- 73Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, Gauthier JM. Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene. EMBO J 1998; 17: 3091–3100.
- 74Piek E, Ju WJ, Heyer J, Escalante-Alcalde D, Stewart CL, Weinstein M, Deng C, Kucherlapati R, Bottinger EP, Roberts AB. Functional characterization of transforming growth factor-βsignaling in Smad2- and Smad3-deficient fibroblasts. J Biol Chem 2001; 276: 19945–1953.
- 75Dennler S, Huet S, Gauthier JM. A short amino acid sequence in MH1 domain is responsible for functional differences between Smad2 and Smad3. Oncogene 1999; 18: 1643–1648.
- 76Ina K, Kitamura H, Tatsukawa S, Fujikura Y. Significance of α-SMA in myofibroblasts emerging in renal tubulointerstitial fibrosis. Histol Histopathol 2011; 26: 855–866.
- 77Dong R, Luo Y, Zheng S. α-SMA overexpression associated with increased liver fibrosis in infants with biliary atresia. J Pediatr Gastroenterol Nutr 2012; 55: 653–656.
- 78Wang J, Yu ZH, Zhou ZYZ, Huang Q, Wang DD, Sun L, Zhu BW, Wei X, He Y, Hong A. Inhibition of α-SMA by the ectodomain of FGFR2c attenuates lung fibrosis. Mole Med 2012; 18: 992–1002.