Role of humoral factors in the development and progression of metabolic syndrome-related kidney diseases

• Project/Area Number: 23591191
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: MUKOYAMA Masashi 京都大学, 医学(系)研究科(研究院), 准教授 (40270558)
• Co-Investigator(Renkei-kenkyūsha): MORI Kiyoshi 京都大学, 医学研究科, 特定准教授 (60343232)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 腎臓学 / 内分泌学 / メタボリック症候群 / Na利尿ペプチド / アルドステロン / 糖尿病性腎症 / 自然炎症 / ノックアウトマウス / ナトリウム利尿ペプチド / 肥満関連腎症 / toll-like receptor 4

Research Abstract

Metabolic syndrome (MetS) represents impaired regulation of humoral or endocrine factors, such as the enhanced renin-angiotensin-aldosterone system. We investigated roles of humoral factors in MetS-associated renal injury.
The natriuretic peptide (ANP and BNP) receptor GC-A is abundantly expressed in renal tubules, but its role in glomerular injury is unknown. When GC-A knockout mice were subjected to aldosterone and high salt, massive proteinuria with marked podocyte injury was observed, which was alleviated with an ARB, antioxidant, or p38 MAPK inhibitor, suggesting their therapeutic potential.
In mouse models of diabetes with dyslipidemia, we found that TLR4 and its ligand MRP8, factors associated with homeostatic inflammation, were markedly upregulated together with worsening of nephropathy. Renal injury was significantly alleviated in TLR4-deficient mice. Expression of MRP8 was also enhanced in advanced human diabetic nephropathy, suggesting its role as a prognostic marker.

Research Products

• [Journal Article] Macrophage-mediated glucolipotoxicity via myeloid-related protein 8/toll-like receptor 4 signaling in diabetic nephropathy (2014)
  • Author(s): Kuwabara, T., Mori, K., Mukoyama, M., Kasahara, M., Yokoi, H., Nakao, K.
  • Journal Title: Clinical and Experimental Nephrology Volume: impress Issue: 4 Pages: 584-592
  • DOI: 10.1007/s10157-013-0922-5
  • NAID: 120005474441
  • Peer Reviewed
• [Journal Article] Do statins play a role in renoprotection? (2014)
  • Author(s): Kasahara M, Nakagawa T, Yokoi H, Kuwabara T, Yasuno S, Mori K, Mukoyama M
  • Journal Title: Ueshima K. Clin Exp Nephrol Volume: 18 Issue: 2 Pages: 282-285
  • DOI: 10.1007/s10157-013-0928-z
  • Peer Reviewed
• [Journal Article] Predictive significance of kidney myeloid-related protein 8 expression in patients with obesity- or type 2 diabetes-associated kidney diseases (2014)
  • Author(s): Kuwabara T, Mori K, Kasahara M, Yokoi H, Imamaki H, Ishii A, Koga K, Sugawara A, Yasuno S, Ueshima K, Morikawa T, Konishi Y, Imanishi M, Nishiyama A, Nakao K, Mukoyama M
  • Journal Title: PloS One Volume: 9 Issue: 2 Pages: e88942-e88942
  • DOI: 10.1371/journal.pone.0088942
  • Peer Reviewed / Open Access
• [Journal Article] Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection (2013)
  • Author(s): Uetake R, Tanaka M, et al.
  • Journal Title: PLoS One. Volume: 9 Issue: 2 Pages: e87667-e87667
  • DOI: 10.1371/journal.pone.0087667
  • Peer Reviewed / Open Access
• [Journal Article] Peritoneal fibrosis and high transport are induced in mildly pre-injured peritoneum by 3,4-dideoxyglucosone-3-ene in mice (2013)
  • Author(s): Yokoi, H., Kasahara, M., Mori, K., Kuwabara, T., Toda, N., Yamada, R., Namoto, S., Yamamoto, T., Seki, N., Souma, N., Yamaguchi, T., Sugawara, A., Mukoyama, M., Nakao, K.
  • Journal Title: Peritoneal Dialysis International Volume: 33(2) Issue: 2 Pages: 143-154
  • DOI: 10.3747/pdi.2011.00033
  • Peer Reviewed
• [Journal Article] Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by Toll-like receptor 4 in mice (2012)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, Ogawa Y, Imamaki H, Kawanishi T, Ishii A, Koga K, Mori KP, Kato Y, Sugawara A, Nakao K
  • Journal Title: Diabetologia Volume: 55:2256-2266 Issue: 8 Pages: 2256-2266
  • DOI: 10.1007/s00125-012-2578-1
  • NAID: 120004225542
  • Peer Reviewed
• [Journal Article] Natriuretic peptide receptor guanylyl cyclase-A protects podocytes from aldosterone-induced glomerular injury (2012)
  • Author(s): Ogawa Y, Mukoyama M, Yokoi H, Kasahara M, Mori K, Kato Y, Kuwabara T, Imamaki H, Kawanishi T, Koga K, Ishii A, Tokudome T, Kishimoto I, Sugawara A, Nakao K
  • Journal Title: J Am Soc Nephrol Volume: 23:1198-1209 Issue: 7 Pages: 1198-1209
  • DOI: 10.1681/asn.2011100985
  • Peer Reviewed
• [Journal Article] Pleiotrophin triggers inflammation and increased peritoneal permeability leading to peritoneal fibrosis (2012)
  • Author(s): Yokoi H, Nakao K, et al
  • Journal Title: Kidney Int. Volume: 81 Issue: 2 Pages: 160-169
  • DOI: 10.1038/ki.2011.305
  • Peer Reviewed
• [Journal Article] Exacerbation of diabetic nephropathy by hyperlipidaemia is mediated by toll-like receptor 4 in mice. (2012)
  • Author(s): Takashige Kuwabara, et al.
  • Journal Title: Diabetologia Volume: 55
  • Peer Reviewed
• [Journal Article] Peritoneal fibrosis and high transport are induced in mildly pre-injured peritoneum by 3,4-dideoxyglucosone-3-ene in mice. (2012)
  • Author(s): Hideki Yokoi, et al.
  • Journal Title: Peritoneal Dialysis International Volume: 32
  • Peer Reviewed
• [Journal Article] Pleiotrophin triggers imflammation and increased peritoneal permeability leading to peritoneal fibrosis. (2012)
  • Author(s): Hideki Yokoi, et al.
  • Journal Title: Kidney International Volume: 81 Pages: 160-169
  • Peer Reviewed
• [Journal Article] Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice (2011)
  • Author(s): M.Naito, K.Ebihara, M.Mukoyama, K.Hosoda, K.Nakao, et al
  • Journal Title: Diabetes Volume: 60(9) Issue: 9 Pages: 2265-73
  • DOI: 10.2337/db10-1795
  • Peer Reviewed
• [Journal Article] Japanese-Western Consensus Meeting on Biomarkers (2011)
  • Author(s): Maisel AS, Nakao K, Ponikowski P, Peacock WF, Yoshimura M, Suzuki T, Tsutamoto T, Filippatos GS, Saito Y, Seino Y, Minamino N, Hirata Y, Mukoyama M, Nishikimi T, Nagai R
  • Journal Title: International Heart Journal Volume: 52 Issue: 5 Pages: 253-265
  • DOI: 10.1536/ihj.52.253
  • NAID: 130001088305
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed
• [Journal Article] Therapeutic impact of leptin on diabetes, diabetic complications, and longevity in insulin-deficient diabetic mice. (2011)
  • Author(s): Masaki Naito, et al.
  • Journal Title: Diabetes Volume: 60 Pages: 2265-2273
  • Peer Reviewed
• [Journal Article] Japanese-Western consensus meeting on biomarkers: executive summary. (2011)
  • Author(s): Alan S. Maisel, et al.
  • Journal Title: International Heart Journal Volume: 52 Pages: 253-265
  • Peer Reviewed
• [Presentation] Na利尿ペプチドと腎・高血圧 (2013)
  • Author(s): 向山政志,横井秀基,森潔
  • Organizer: 第43回日本腎臓学会西部学術大会(シンポジウム)
  • Place of Presentation: 松山
• [Presentation] Na利尿ペプチド系と腎・高血圧性疾患 (2013)
  • Author(s): 向山政志,横井秀基,森潔
  • Organizer: 第49回高血圧関連疾患モデル学会(シンポジウム)
  • Place of Presentation: 東京
• [Presentation] Macrophage-mediated glucolipotoxicity via MRP8/TLR4 signaling in diabetic nephropathy (2013)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, et al.
  • Organizer: 2013年世界腎臓学会
  • Place of Presentation: 香港
• [Presentation] High fat diet- or fasting-induced renal lipid deposition is differentially associated with changes in systemic and renal lipid-modulating factors (2013)
  • Author(s): Mori KP, Mori K, Mukoyama M, et al.
  • Organizer: 2013年世界腎臓学会
  • Place of Presentation: 香港
• [Presentation] p38 MAPK signaling mediates aldosterone-induced renal injury in natriuretic peptide receptor (GC-A)-deficient mice (2013)
  • Author(s): Kato Y, Mukoyama M, Yokoi H, et al.
  • Organizer: ISARSH2013
  • Place of Presentation: 仙台
• [Presentation] Na利尿ペプチド系と腎・高血圧性疾患 (2013)
  • Author(s): 向山政志
  • Organizer: 第49回高血圧関連疾患モデル学会
  • Place of Presentation: 日大会館
  • Invited
• [Presentation] Na利尿ペプチドと腎・高血圧 (2013)
  • Author(s): 向山政志
  • Organizer: 第43回日本腎臓学会西部学術大会
  • Place of Presentation: 松山全日空ホテル
  • Invited
• [Presentation] 肥満症と高血圧、腎障害-炎症とレニン・アンジオテンシン系の意義- (2012)
  • Author(s): 向山政志
  • Organizer: 第33回日本肥満学会
  • Place of Presentation: 京都
  • Invited
• [Presentation] 肥満と炎症、レニン・アンジオテンシン系 (2012)
  • Author(s): 向山政志,森潔,桒原孝成,今牧博貴,細田公則,中尾一和
  • Organizer: 第35回日本高血圧学会(シンポジウム)
  • Place of Presentation: 名古屋
• [Presentation] Macrophage-mediated glucolipotoxicity contributes to progression of diabetic nephropathy through MRP8/TLR4 signaling (2012)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, et al.
  • Organizer: 第45回米国腎臓学会
  • Place of Presentation: サンディエゴ、アメリカ
• [Presentation] p38 MAP kinase mediates aldosterone-induced podocyte injury in natriuretic peptide receptor (GC-A)-deficient mice (2012)
  • Author(s): Kato Y, Mukoyama M, Yokoi H, et al.
  • Organizer: 第45回米国腎臓学会
  • Place of Presentation: サンディエゴ、アメリカ
• [Presentation] Alteration of renal lipid deposition and gene expression induced by fasting and high-fat diet feeding (2012)
  • Author(s): Mori KP, Mori K, Mukoyama M, et al.
  • Organizer: 第45回米国腎臓学会
  • Place of Presentation: サンディエゴ、アメリカ
• [Presentation] Role of p38 MAPK in aldosterone-induced glomerular injury in natriuretic peptide receptor-A deficient mice (2012)
  • Author(s): Kato Y, Mukoyama M, Yokoi H, et al.
  • Organizer: 第24回国際高血圧学会
  • Place of Presentation: シドニー、オーストラリア
• [Presentation] 肥満と炎症、レニン・アンジオテンシン系 (2012)
  • Author(s): 向山政志
  • Organizer: 第35回日本高血圧学会総会
  • Place of Presentation: 愛知県名古屋市ウェスティンナゴヤキャッスル
  • Invited
• [Presentation] 肥満症と高血圧、腎障害－炎症とレニン・アンジオテンシン系の意義－ (2012)
  • Author(s): 向山政志
  • Organizer: 第33回日本肥満学会
  • Place of Presentation: ホテルグランヴィア京都
  • Invited
• [Presentation] Na利尿ペプチドとNgal-最新の話題- (2011)
  • Author(s): 向山政志,森潔,笠原正登,中尾一和
  • Organizer: 第15回日本心血管内分泌代謝学会(シンポジウム)
  • Place of Presentation: 豊中
• [Presentation] 脂質代謝異常による糖尿病性腎症悪化の新たな分子機構 (2011)
  • Author(s): 向山政志,森潔,桒原孝成,中尾一和
  • Organizer: 第41回日本腎臓学会西部学術大会(シンポジウム)
  • Place of Presentation: 徳島
• [Presentation] Aggravation of diabetic nephropathy by hyperlipidemia is mediated by MRP8/TLR4 signaling in macrophages (2011)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, et al.
  • Organizer: 第44回米国腎臓学会
  • Place of Presentation: フィラデルフィア、アメリカ
• [Presentation] Blockade of p38 MAPK pathway ameliorates aldosterone-induced renal injury in guanylyl cyclase-A deficient mice (2011)
  • Author(s): Kato Y, Mukoyama M, Yokoi H, et al.
  • Organizer: 第44回米国腎臓学会
  • Place of Presentation: フィラデルフィア、アメリカ
• [Presentation] Toll-like receptor 4-mediated, hyperinsulinemia- independent progression of diabetic nephropathy by hyperlipidemia (2011)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, et al.
  • Organizer: 第71回米国糖尿病学会
  • Place of Presentation: サンディエゴ、アメリカ
• [Presentation] Hyperlipidemia promotes diabetic renal injury via TLR4 signaling (2011)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, et al.
  • Organizer: 2011年世界腎臓学会
  • Place of Presentation: バンクーバー、カナダ
• [Presentation] Na利尿ペプチドとNgal－最新の話題－ (2011)
  • Author(s): 向山政志
  • Organizer: 第15回日本心血管内分泌代謝学会学術総会(招待講演)
  • Place of Presentation: 大阪府豊中市千里ライフサイエンスセンター
• [Remarks]
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp
• [Patent(Industrial Property Rights)] 腹膜癒着防止用医薬組成物 (2011)
  • Inventor(s): 中尾一和、横井秀基、向山政志、笠原正登、古谷真優美
  • Industrial Property Rights Holder: 国立大学法人京都大学、第一三共株式会社
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2011-049845
  • Filing Date: 2011-03-08
  • Overseas