Elucidation of the pathogenic mechanism of diabetic nephropathy by oral microorganism-derived blood TLR ligand and development for prevention

• Project/Area Number: 15H05060
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Social dentistry
• Research Institution: Okayama University (2017); Fukuoka Dental College (2015-2016)
• Principal Investigator: SAWA YOSHIHIKO 岡山大学, 医歯薬学総合研究科, 教授 (70271666)
• Co-Investigator(Kenkyū-buntansha): 加藤 幸成 東北大学, 医学系研究科, 教授 (00571811) ; 畠山 雄次 福岡歯科大学, 口腔歯学部, 教授 (40302161) ; 坂上 竜資 福岡歯科大学, 口腔歯学部, 教授 (50215612) ; 福島 秀文 東北大学, 歯学研究科(研究院), 准教授 (70412624)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2017: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2016: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2015: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
• Keywords: 歯周病 / 糖尿病性腎症 / toll-like receptor / Porphyromonas gingivalis / 糸球体硬化 / lipopolysaccharide / 歯周疾患 / 歯学 / 終末糖化産物 / 糸球体内皮細胞 / TGF-β / I型コラーゲン / 糖尿病マウス / 口腔微生物 / P. gingivalis / 1型コラーゲン

Outline of Final Research Achievements

Diabetes is known to increase the possibility of becoming nephropathy when it comes to periodontitis, but the mechanism is not known. In an experiment using diabetic mice, we found that blood vessels of a urine generating device, called glomeruli of the kidney, express 'toll-like receptors' that recognize bacterial components when it comes to diabetes. We also found that injection of periodontal disease pathogen into mucosa of diabetic mouse oral cavity causes nephropathy. It is thought that germs of periodontal disease enter the blood vessels of the oral cavity, go around the body, enter the kidney and bind to the receptor and cause nephropathy. In periodontitis, bacteria easily enter the blood vessel with tooth brushing. For people with diabetes, prevention of periodontitis is considered to prevent the diabetic nephropathy.

Research Products

• [Int'l Joint Research] Richard Peters Darveau/Department of Periodontics/University of Washington(米国)
• [Int'l Joint Research] Thao T. To/Department of Periodontics/University of Washington(米国)
• [Journal Article] LpMab-23-recognizing cancer-type podoplanin is a novel predictor for a poor prognosis of early stage tongue cancer. (2018)
  • Author(s): Miyazaki, A., Nakai, H., Sonoda, T., Kaneko, M.K., Kato, Y., Sawa, Y., Hiratsuka, H.
  • Journal Title: Oncotarget Volume: 9 Issue: 30 Pages: 21156-21165
  • DOI: 10.18632/oncotarget.24986
  • Peer Reviewed / Open Access
• [Journal Article] Expression and Dynamics of Podoplanin in Cultured Osteoblasts with Mechanostress and Mineralization Stimulus (2018)
  • Author(s): Takenawa, T., Kanai, T., Kitamura, T., Yoshimura, Y., Sawa, Y., Iida, J.
  • Journal Title: ACTA HISTOCHEMICA ET CYTOCHEMICA Volume: 51 Issue: 1 Pages: 41-52
  • DOI: 10.1267/ahc.17031
  • NAID: 130006405040
  • ISSN: 0044-5991, 1347-5800
  • Peer Reviewed / Open Access
• [Journal Article] The promotion of nephropathy by Porphyromonas gingivalis lipopolysaccharide via toll-like receptors. (2017)
  • Author(s): Kajiwara, K., Takata, S., To, T., Takara, K., Hatakeyama, Y., Tamaoki, S., Darveau, R.P., Ishikawa, H., Sawa, Y.
  • Journal Title: Diabetology & Metabolic Syndrome Volume: 9 Issue: 1 Pages: 73-73
  • DOI: 10.1186/s13098-017-0271-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Morphological study of tooth development in podoplanin-deficient mice. (2017)
  • Author(s): Takara, K., Maruo, N., Oka, K., Kaji, C., Hatakeyama, Y., Sawa, N., Kato, Y., Sawa, Y.
  • Journal Title: PLoS One Volume: 12 Issue: 2 Pages: e0171912-e0171912
  • DOI: 10.1371/journal.pone.0171912
  • Peer Reviewed / Open Access
• [Journal Article] Effects of a Chemically Synthesized Leucine-Rich Amelogenin Peptide (csLRAP) on Chondrogenic and Osteogenic Cells (2017)
  • Author(s): Matsuda, Y., Hatakeyama, Y., Nakashima, K., Kamogashira, N., Hatakeyama, J., Sawa, Y.
  • Journal Title: Journal of Hard Tissue Biology Volume: 26 Issue: 1 Pages: 51-60
  • DOI: 10.2485/jhtb.26.51
  • NAID: 130005188392
  • ISSN: 1341-7649, 1880-828X
  • Peer Reviewed / Open Access
• [Journal Article] Distinct Role of Transforming Growth Factor-Beta 1 and Fibroblast Growth Factors in Human Amelobastoma Epithelial Cell Proliferation (2017)
  • Author(s): Matsuda Y, Kamogashira N, Hatakeyama Y, Mikami T, Nakashima K, Hatakeyama J, Tamaoki S, Sawa Y, Ishikawa H
  • Journal Title: Biochemistry and Molecular Biology Volume: 2(1) Issue: 1 Pages: 1-5
  • DOI: 10.11648/j.bmb.20170201.11
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of TLR4 blocking on diabetic nephropathy promoted by the Porphyromonas gingivalis lipopolysaccharide. (2017)
  • Author(s): Kajiwara, K., Takata S., To, T., Takara, K., Hatakeyama, Y., Tamaoki, S., Darveau, R., Ishikawa, I., Sawa, Y.
  • Journal Title: Diabetology & Metabolic Syndrome Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Differentiation of Apical Bud Cells in a Newly Developed Apical Bud Transplantation Model Using GFP Transgenic Mice as Donor. (2016)
  • Author(s): Maruo N, Sakagami R, Yoshinaga Y, Okamura K, Sawa Y.
  • Journal Title: PLoS One Volume: 11(3)
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel Monoclonal Antibody LpMab-17 Developed by CasMab Technology Distinguishes Human Podoplanin from Monkey Podoplanin. (2016)
  • Author(s): Kato Y, Ogasawara S, Oki H, Honma R, Takagi M, Fujii Y, Nakamura T, Saidoh N, Kanno H, Umetsu M, Kamata S, Kubo H, Yamada M, Sawa Y, Morita K, Harada H, Suzuki H, Kaneko MK.
  • Journal Title: Monoclon Antib Immunodiagn Immunother Volume: 35(2) Pages: 109-116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Effects of TLR4 blocking on diabetic nephropathy promoted by the Porphyromon as gingivalis lipopolysaccharide (2017)
  • Author(s): 梶原、高田、藤田、高良、畠山、玉置、石川、沢
  • Organizer: 第65回国際歯科研究学会日本部会（JADR）学術大会
• [Presentation] The morphological investigation of head and neck organs in the systemic podoplanin knockout mice (2016)
  • Author(s): Kaji C, Takara K, Hatakeyama Y, Kojima H, Sawa Y.
  • Organizer: International Association of Dental research
  • Place of Presentation: Seoul
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Porphyromonas gingivalis lipopolysaccharide promote diabetic nephropathy through TLR2 (2016)
  • Author(s): Kajiwara K, Takata S, Hatakeyama Y, Ishikawa H, Sawa Y.
  • Organizer: International Association of Dental research
  • Place of Presentation: Seoul
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] The expression of podoplanin and bone-associated proteins in the osteoblasts and craniofacial osteocytes with mechanical stress (2016)
  • Author(s): Kanai K, Sawa Y.
  • Organizer: International Association of Dental research
  • Place of Presentation: Seoul
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Study for the apical bud differentiation model using green mice (2016)
  • Author(s): Maruo N, Sakagami R, Yoshinaga Y, Sawa Y.
  • Organizer: International Association of Dental research
  • Place of Presentation: Seoul
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] The distribution of podoplanin in the tooth and craniofacial bone (2016)
  • Author(s): Takara K, Kaji C, Hatakeyama Y, Kojima H, Sawa Y.
  • Organizer: International Association of Dental research
  • Place of Presentation: Seoul
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] The cytokine inductions in glomerular endothelial cells with Porphyromonas gingivalis lipopolysaccharide through TLR2 (2016)
  • Author(s): Takata S, Kajiwara K, Hatakeyama Y, Ishikawa H, Sawa Y.
  • Organizer: International Association of Dental research
  • Place of Presentation: Seoul
  • Year and Date: 2016-06-22
  • Int'l Joint Research