The effects of food protein-derived metabolite, indoxyl sulfate, on progression of renal disease.

• Project/Area Number: 23700830
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Applied health science
• Research Institution: Hokkaido University (2012); Nagoya University (2011)
• Principal Investigator: SHIMIZU Hidehisa 北海道大学, 大学院・農学研究院, 特任講師 (10547532)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 慢性腎不全 / 尿毒症物質 / トリプトファン代謝物 / インドキシル硫酸 / 細胞老化 / 線維化 / 炎症反応 / 繊維化

Research Abstract

In patients with chronic kidney disease (CKD), serum indoxyl sulfate is elevated. Therefore, the present study examined what molecules are activated and expressed by indoxyl sulfate, and how indoxyl sulfate promotes CKD. Indoxyl sulfate activated ERK, p38, JNK, NF-?B, p53, Stat3, and CREB in proximal tubular cells. In addition, the expression of NOX4, TGF-?1, Smad3, ?-SMA, MCP-1, ICAM-1, and angiotensinogen was upregulated. Current study demonstrated that indoxyl sulfate induced macrophage infiltration, cellular senescence, and fibrosis through activation and expression of above-mentioned factors in process of CKD progression.

Research Products

• [Journal Article] Organochlorine pesticides and heavy metals in fish from Lake Awassa; Ethiopia: Insights from stable isotope analysis. (2013)
  • Author(s): Yared BY, Ikenaka Y, Nakayama SMM, Saengtienchai A, Watanabe K, Ishizuka M
  • Journal Title: Chemosphere Volume: 91 Pages: 857-863
  • Peer Reviewed
• [Journal Article] Accumulation and biological effects of metals in wild rats in mining areas of Zambia (2013)
  • Author(s): Nakayama SMM, Ikenaka Y, Hamada K, Muzandu K, Choongo K, Yabe J, Umemura T, Ishizuka M.
  • Journal Title: Environmental Monitoring and Assessment Volume: 185 Pages: 4907-4918
  • Peer Reviewed
• [Journal Article] Metal distribution in tissues of free-range chickens near a lead-zinc mine in Kabwe, Zambia. (2013)
  • Author(s): Yabe J, Nakayama SMM, Ikenaka Y, Muzandu K, Choongo K, Mainda G, Kabeta N, Ishizuka M, Umemura T.
  • Journal Title: Environ Toxicol Chem Volume: 32(1) Pages: 189-92
  • Peer Reviewed
• [Journal Article] GIS-based source estimation of Cu pollution in Lake Itezhi-tezhi and metal accumulation profiles in Oreochromis spp. from both field and laboratory studies (2013)
  • Author(s): Shouta M.M. Nakayama, Yoshinori Ikenaka, Kaampwe Muzandu, Kennedy Choongo, John Yabe, Taro Muroya, Shigeho Ijiri, Masao Minagawa, Takashi Umemura, Mayumi Ishizuka.
  • Journal Title: Arch Environ Contam Toxicol Volume: 64(1) Pages: 119-29
  • Peer Reviewed
• [Journal Article] Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB. (2013)
  • Author(s): Bolati D, Shimizu H, Yisireyili M, Nishijima F, Niwa T.
  • Journal Title: BMC Nephrol. Volume: 14 Issue: 1 Pages: 56-56
  • DOI: 10.1186/1471-2369-14-56
  • Peer Reviewed
• [Journal Article] CREB, NF-κB, and NADPH oxidase coordinately upregulate indoxyl sulfate-induced angiotensinogen expression in proximal tubular cells. (2013)
  • Author(s): Shimizu H, Saito S, Higashiyama Y, Nishijima F, Niwa T.
  • Journal Title: Am J Physiol Cell Physiol. Volume: 304 Issue: 7 Pages: C685-C692
  • DOI: 10.1152/ajpcell.00236.2012
  • Peer Reviewed
• [Journal Article] Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells. (2013)
  • Author(s): Shimizu H, Yisireyili M, Nishijima F, Niwa T.
  • Journal Title: Am J Nephrol. Volume: 37 Issue: 2 Pages: 97-103
  • DOI: 10.1159/000346420
  • Peer Reviewed
• [Journal Article] Indoxyl sulfate upregulates renal expression of ICAM-1 via production of ROS and activation of NF-κB and p53 in proximal tubular cells. (2013)
  • Author(s): Shimizu H, Yisireyili M, Higashiyama Y, Nishijima F, Niwa T.
  • Journal Title: Life Sci. Volume: 92 Issue: 2 Pages: 143-148
  • DOI: 10.1016/j.lfs.2012.11.012
  • Peer Reviewed
• [Journal Article] Cytochrome P450 3A mRNA expression along goat and rat gastrointestinal tracts. (2012)
  • Author(s): Dominic MUREITHI, Wageh Sobhy DARWISH, Yoshinori IKENAKA, Laetitia KANJA, Mayumi ISHIZUKA.
  • Journal Title: Jpn. J. Vet. Res Volume: 60(4) Pages: 205-10
  • Peer Reviewed
• [Journal Article] Accumulation of metals in the liver and kidneys of cattle from agricultural areas in Lusaka, Zambia (2012)
  • Author(s): Yabe J, Nakayama SMM, Ikenaka Y, Muzandu K, Ishizuka M, Umemura T.
  • Journal Title: J Vet Med Sci Volume: 74(10) Pages: 1345-7
  • Peer Reviewed
• [Journal Article] The nucleotide sequence of metallothioneins (MT) in liver of the Kafue lechwe (Kobus leche kafuensis) and their potential as biomarkers of heavy metal pollution of the Kafue River. (2012)
  • Author(s): M'kandawire E, Syakalima M, Muzandu K, Pandey G, Simuunza M, Nakayama SM, Kawai YK, Ikenaka Y, Ishizuka M.
  • Journal Title: Gene. Volume: 506(2) Pages: 310-6
  • Peer Reviewed
• [Journal Article] Effects of environmental lead contamination on cattle in a lead/zinc mining area: changes in cattle immune systems on exposure to lead in vivo and in vitro. (2012)
  • Author(s): Ikenaka Y, Nakayama SMM, Muroya T, Yabe J, Konnai S, Darwish WS, Muzandu K, Choongo K, Mainda G, Teraoka H, Umemura T, Ishizuka M.
  • Journal Title: Environ Toxicol Chem Volume: 31(10) Pages: 2300-5
  • Peer Reviewed
• [Journal Article] Transcriptional profiling of inflammatory cytokine genes in African buffaloes (Syncerus caffer) infected with Theileria parva. (2012)
  • Author(s): Okagawa T, Konnai S, Mekata H, Githaka N, Suzuki S, Kariuki E, Gakuya F, Kanduma E, Shirai T, Ikebuchi R, Ikenaka Y, Ishizuka M, Murata S, Ohashi K.
  • Journal Title: Vet Immunol Immunopathol Volume: 148(3-4) Pages: 373-9
  • Peer Reviewed
• [Journal Article] Metal and metalloid levels and bio-accumulation characteristics in soil, sediment, land plants and hippopotami (Hippopotamus amphibius L) from the South Luangwa National Park, Zambia. (2012)
  • Author(s): Nakayama SM, Ikenaka Y, Muzandu K, Choongo K, M'kandawire E, Yasuda J,Ishizuka M.
  • Journal Title: Ecotoxicol Environ Saf Volume: 80 Pages: 333-8
  • Peer Reviewed
• [Journal Article] Molecular cloning and characterization of Th1 and Th2 cytokines of African buffalo (Syncerus caffer). (2012)
  • Author(s): Suzuki S, Konnai S, Okagawa T, Githaka NW, Kariuki E, Gakuya F, Kanduma E, Shirai T, Ikebuchi R, Ikenaka Y, Ishizuka M, Murata S, Ohashi K.
  • Journal Title: Int J Immunogenet Pages: 170-82
  • Peer Reviewed
• [Journal Article] Stat3 contributes to indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence. (2012)
  • Author(s): Shimizu H, Yisireyili M, Nishijima F, Niwa T.
  • Journal Title: Am J Nephrol. Volume: 36 Issue: 2 Pages: 184-189
  • DOI: 10.1159/000341515
  • Peer Reviewed
• [Journal Article] Indoxyl sulfate upregulates renal expression of MCP-1 via production of ROS and activation of NF-κB, p53, ERK, and JNK in proximal tubular cells. (2012)
  • Author(s): Shimizu H, Bolati D, Higashiyama Y, Nishijima F, Shimizu K, Niwa T.
  • Journal Title: Life Sciences Volume: 90 Pages: 525-530
  • Peer Reviewed
• [Journal Article] 野生動物の化学物質感受性と生体防御機構 (2011)
  • Author(s): 池中良徳、石塚真由美
  • Journal Title: 安全工学 Volume: 50(2) Pages: 80-80
  • Peer Reviewed
• [Journal Article] Phase-II conjugation ability for PAH metabolism in amphibians: Characteristics and inter-species differences. (2011)
  • Author(s): Ueda H, Ikenaka Y, Nakayama SM, Tanaka-Ueno T, Ishizuka M.
  • Journal Title: Aquat Toxicol Volume: 105(3-4) Pages: 337-343
  • Peer Reviewed
• [Journal Article] Metal and metalloid contamination in roadside soil and wild rats around a Pb-Zn mine in Kabwe, Zambia. (2011)
  • Author(s): Nakayama SMM, Ikenaka Y, Hamada K, Muzandu K, Choongo K, Teraoka H, Mizuno N, Ishizuka M.
  • Journal Title: Environmental Pollution Volume: 159 Pages: 175-18
  • Peer Reviewed
• [Journal Article] Occurrence, distribution and ecological risk assessment of DDTs and heavy metals in surface sediments from Lake Awassa ?Ethiopian Rift Valley Lake.
  • Author(s): Yohannes YB, Ikenaka Y, Saengtienchai A, Watanabe KP, Nakamyama SMM, Ishizuka M.
  • Journal Title: Environ Sci Pollut Res Volume: (in press)
  • Peer Reviewed
• [Presentation] Effect of mining activity on wild and domestic animals: Case study of lead ? zink mining area, Kabwe, Zambia (2013)
  • Author(s): Yoshinori Ikenaka
  • Organizer: 日本学術会議北海道地区会議主催学術講演会
  • Place of Presentation: 北海道大学学術交流会館小講堂
  • Year and Date: 2013-03-01
• [Presentation] 両生類の異物代謝機構の特徴と種差 (2012)
  • Author(s): 池中良徳
  • Organizer: 第21回環境化学討論会
  • Place of Presentation: 愛媛県県民文化会館(ひめぎんホール)
• [Presentation] 鳥類における薬物代謝の特徴:ピレンをモデル化合物として (2012)
  • Author(s): 池中良徳
  • Organizer: 第21回環境化学討論会
  • Place of Presentation: 愛媛県県民文化会館(ひめぎんホール)
• [Presentation] 薬物代謝第II相抱合反応の種差:多環芳香族炭化水素の抱合反応と哺乳動物で観察された種差 (2012)
  • Author(s): 池中良徳
  • Organizer: 第21回環境化学討論会
  • Place of Presentation: 愛媛県県民文化会館(ひめぎんホール)
• [Presentation] 腎血管系の老化に対する尿毒症物質インドキシル硫酸の影響 (2012)
  • Author(s): 清水英寿
  • Organizer: 創薬薬理フォーラム 第20回シンポジウム
  • Place of Presentation: 東京 （ 日本薬学会 長井記念館）
  • Invited
• [Presentation] Stat3 is involved in indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence in proximal tubular cells. (2012)
  • Author(s): Niwa, T., Nishijima, F., Shimizu, H.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Diego, USA (San Diego Convention Center)
• [Presentation] Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB. (2012)
  • Author(s): Niwa, T., Bolati, D., Yisireyili, M., Nishijima, F., Shimizu, H.
  • Organizer: American Society of Nephrology
  • Place of Presentation: San Diego, USA (San Diego Convention Center)
• [Presentation] Indoxyl sulfate upregulates renal expression of ICAM-1 via production of ROS and activation of NF-κB and p53 in proximal tubular cells. (2012)
  • Author(s): Shimizu, H., Niwa. T.
  • Organizer: 16th International Congress on Nutrition and Metabolism in Renal Disease
  • Place of Presentation: Honolulu, USA (Hilton Hawaiian Village)
• [Presentation] インドキシル硫酸によるMCP‐1の発現メカニズムの解析 (2012)
  • Author(s): 清水英寿, デリナル ポラテ, ムテリフ グリヌル, アデリベキ イリシャテ, イスリ メメット, 下山泰彦, 東山幸弘, 西島冬彦, 丹羽利充
  • Organizer: 第55回 日本腎臓学会
  • Place of Presentation: 横浜 （ パシフィコ横浜）
• [Presentation] インドキシル硫酸によるTGF‐β1の発現制御機構及びTGF‐β1とのクロストークの検討 (2012)
  • Author(s): 清水英寿, デリナル ポラテ, ムテリフ グリヌル, アデリベキ イリシャテ, イスリ メメット, 下山泰彦, 東山幸弘, 西島冬彦, 丹羽利充
  • Organizer: 第55回 日本腎臓学会
  • Place of Presentation: 横浜（ パシフィコ横浜）
• [Book] 獣医学・応用動物科学系学生のための野生動物学 (2013)
  • Author(s): 村田浩一 坪田敏男
  • Publisher: 野生動物と環境汚染
• [Remarks] 北海道大学アフリカ研究会
  • URL: http://aa.vetmed.hokudai.ac.jp/africa/
• [Remarks] 北海道大学大学院獣医学研究科毒性学教室
  • URL: http://tox.vetmed.hokudai.ac.jp/