Translational research and clinical application of the natriuretic peptide system in the kidney.

• Project/Area Number: 20590956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: MUKOYAMA Masashi Kyoto University, 医学研究科, 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): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腎臓学 / 慢性賢臓病 / トランスレーショナルリサーチ / Na利尿ペプチド / ノックアウトマウス / アルドステロン / 糖尿病性賢症 / 蛋白尿 / ポドサイト / 慢性腎臓病 / トランスジェニックマウス / 糖尿病性腎症 / 結合組織成長因子(CTGF) / 線維化

Research Abstract

Natriuretic peptide family (ANP, BNP, and CNP) exert potent diuretic, natriuretic and vasorelaxing properties, as well as the inhibition of the renin-angiotensin-aldosterone system. We investigated the role of natriuretic peptides in renal disease and its complications.
1. Preparation of CNP-transgenic mice (CNP-Tg) and effects of CNP on renal injury :
CNP acts as a local hormone in the vessel, bone and kidney. Human SAP promoter-driven CNP-Tg exhibited enhanced bone growth as a result of excess circulating CNP. CNP-Tg showed ameliorated renal fibrosis and macrophage infiltration upon obstructive nephropathy model.
2. Role of GC-A (a receptor for ANP and BNP) and aldosterone in glomerular injury :
GC-A is expressed abundantly 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 the MR antagonist, ARB or antioxidant.
3. Role of ANP and BNP in peritoneal sclerosis :
Peritoneal sclerosis is a serious complication in chronic peritoneal dialysis, but the effective treatment is not established yet. Subcutaneous ANP administration as well as chronic BNP excess in transgenic mice effectively ameliorated peritoneal adhesion in a mouse model of peritoneal sclerosis.
These results indicate that natriuretic peptides will have a various therapeutic potential in renal disease and related pathophysiological conditions.

Research Products

• [Journal Article] Circulating C-type natriuretic peptide (CNP) rescues chondrodysplastic CNP knockout mice from their impaired skeletal growth and early death. (2010)
  • Author(s): Fujii T, Komatsu Y, Yasoda A, Kondo E, Yoshioka T, Nambu T, Kanamoto N, Miura M, Tamura N, Arai H, Mukoyama M, Nakao K
  • Journal Title: Endocrinology 151 Pages: 4381-4388
  • Peer Reviewed
• [Journal Article] Podocyte-specific expression of tamoxifeninducible Cre recombinase in mice. (2010)
  • Author(s): Yokoi H, Kasahara M, Mukoyama M, Mori K, Kuwahara K, Fujikura J, Arai Y, Saito Y, Ogawa Y, Kuwabara T, Sugawara A, Nakao K.
  • Journal Title: Nephrol Dial Transplant 25 Pages: 2120-2124
  • Peer Reviewed
• [Journal Article] Circulating C-type natriuretic peptide (CNP) rescues chondrodysplastic CNP knockout mice from their impaired skeletal growth and early death. (2010)
  • Author(s): Toshihito Fujii, et al.
  • Journal Title: Endocrinology Volume: 151 Pages: 4381-4388
  • Peer Reviewed
• [Journal Article] Podocyte-specific expression of tamoxifen-inducible Cre recombinase in mice. (2010)
  • Author(s): Hideki Yokoi, et al.
  • Journal Title: Nephrology, Dialysis and Transplantation Volume: 25 Pages: 2120-2124
  • Peer Reviewed
• [Journal Article] Searching for novel intercellular signal-transducing molecules in the kidney and their clinical application. (2010)
  • Author(s): Kiyoshi Mori, et al.
  • Journal Title: Clinical and Experimental Nephrology Volume: 14 Pages: 523-527
  • NAID: 10029321075
  • Peer Reviewed
• [Journal Article] Impact of left ventricular hypertrophy on the time-course of renal function in hypertensive patients : A subanalysis of the CASE-J trial. (2010)
  • Author(s): Kenji Ueshima, et al.
  • Journal Title: Circulation Journal Volume: 74 Pages: 2132-2138
  • Peer Reviewed
• [Journal Article] Podocyte-specific expression of tamoxifen-inducible Cre recombinase in mice. (2010)
  • Author(s): Hideki Yokoi, et al.
  • Journal Title: Nephrology, Dialysis and Transplantation 25(印刷中)
  • Peer Reviewed
• [Journal Article] Translational research of novel hormones : Lessons from animal models and rare human diseases to common human diseases. (2009)
  • Author(s): Nakao K, Yasoda A, Ebihara K, Hosoda K, Mukoyama M
  • Journal Title: J Mol Med 87 Pages: 1029-1039
  • Peer Reviewed
• [Journal Article] Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. (2009)
  • Author(s): Kake T, Kitamura H, Adachi Y, Yoshioka T, Watanabe T, Matsushita H, Fujii T, Kondo E, Tachibe T, Kawase Y, Jishage K, Yasoda A, Mukoyama M, Nakao K
  • Journal Title: Am J Physiol Endocr Metab 297
  • Peer Reviewed
• [Journal Article] Reduction in urinary excretion of neutrophil gelatinase-associated lipocalin by angiotensin receptor blockers in hypertensive patients. (2009)
  • Author(s): Kasahara M, Mori K, Satoh N, Kuwabara T, Yokoi H, Shimatsu A, Sugawara A, Mukoyama M, Nakao K
  • Journal Title: Nephrol Dial Transplant 24 Pages: 2608-2609
  • Peer Reviewed
• [Journal Article] Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. (2009)
  • Author(s): Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, Yoshioka T, Ogawa Y, Imamaki H, Kusakabe T, Ebihara K, Omata M, Satoh N, Sugawara A, Barasch J, Nakao K
  • Journal Title: Kidney Int 75 Pages: 285-294
  • NAID: 120005678177
  • Peer Reviewed
• [Journal Article] Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. (2009)
  • Author(s): Takei Kake, et al.
  • Journal Title: American Journal of Physiology Endocrinology and Metabolism 297
  • Peer Reviewed
• [Journal Article] Translational research of novel hormones : Lessons from animal models and rare human diseases to common human diseases. (2009)
  • Author(s): Kazuwa Nakao, et al.
  • Journal Title: Journal of Molecular Medicine 87 Pages: 1029-1039
  • Peer Reviewed
• [Journal Article] Reduction in urinary excretion of neutrophil gelatinase-associated lipocalin by angiotensin receptor blockers in hypertensive patients. (2009)
  • Author(s): Masato Kasahara, et al.
  • Journal Title: Nephrology, Dialysis and Transplantation 24 Pages: 2608-2609
  • Peer Reviewed
• [Journal Article] Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to gelomeruli, proximal tubules, and distal nephrons. (2009)
  • Author(s): Takashige Kuwabara, et al.
  • Journal Title: Kidney International 75 Pages: 285-294
  • Peer Reviewed
• [Journal Article] Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal- regulated kinase activation and renal fibrosis. (2008)
  • Author(s): Nagae T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Suganami T, Sawai K, Yoshioka T, Koshikawa M, Saito Y, Ogawa Y, Kuwabara T, Tanaka I, Sugawara A, Kuwahara T, Nakao K
  • Journal Title: Kidney Int 74 Pages: 70-80
  • Peer Reviewed
• [Journal Article] Overexpression of connective tissue growth factor in podocytes worsens diabetic neohropathy in mice. (2008)
  • Author(s): Hideki Yokoi, et al.
  • Journal Title: Kidney International 73 Pages: 446-455
  • Peer Reviewed
• [Journal Article] Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis. (2008)
  • Author(s): Tetsuya Nagae, et al.
  • Journal Title: Kidney International 74 Pages: 70-80
  • Peer Reviewed
• [Presentation] Atrial natriuretic peptide prevents peritoneal adhesion formation with inhibiting macrophage and CD3-positive cell infiltration. (2010)
  • Author(s): Yokoi H, Kasahara M, Mori K, Kuwabara T, Imamaki H, Kawanishi T, Koga K, Ishii A, Mori K, Kato Y, Sugawara A, Mukoyama M, Nakao K
  • Organizer: 第43回米国腎臓学会学術集会
  • Place of Presentation: デンバー、アメリカ
  • Year and Date: 2010-11-18
• [Presentation] Renoprotective role of natriuretic peptide family in various nephropathy models and its potential to clinical application. (2010)
  • Author(s): Mukoyama M, Mori K, Kasahara M, Yokoi H, Ogawa Y, Kuwabara T, Nakao K
  • Organizer: 第12回アジア太平洋腎臓学会
  • Place of Presentation: ソウル、韓国
  • Year and Date: 2010-06-07
• [Presentation] Renoprotective role of natriuretic peptide familiy in various nephropathy model and its potential to clinical application. (2010)
  • Author(s): Masashi Mukoyama
  • Organizer: 12th Asian-Pacific Congers of Nephrology
  • Place of Presentation: ソウル国際会議場(ソウル市)韓国
  • Year and Date: 2010-06-07
• [Presentation] Natriuretic peptide receptor guanylyl cyclase-A signaling exerts antagonistic effects on the local renin-angiotensin- aldosterone system in kidney. (2010)
  • Author(s): Ogawa Y, Mukoyama M, Yokoi H, Kasahara M, Mori K, Yoshioka T, Saito Y, Kuwabara T, Imamaki H, Kawanishi T, Koga K, Ishii A, Kishimoto I, Sugawara A, Nakao K
  • Organizer: 国際腎臓学会Nexus Symposium 2010
  • Place of Presentation: 京都
  • Year and Date: 2010-04-16
• [Presentation] Role of cardiovascular hormones in renal disease. (2010)
  • Author(s): Mukoyama M, Mori K, Kasahara M, Yokoi H, Nakao K
  • Organizer: 第14回国際内分泌学会(シンポジウム)
  • Place of Presentation: 京都
  • Year and Date: 2010-03-29
• [Presentation] Role of cardiovascular hormones in renal disease. (2010)
  • Author(s): Masashi Mukoyama
  • Organizer: 14th International Congress of Endocrinology
  • Place of Presentation: 国立京都国際会館(京都市)
  • Year and Date: 2010-03-29
• [Presentation] Protective effects of natriuretic peptide receptor guanylyl cyclase-A signaling on aldosteroneinduced glomerular injury. (2009)
  • Author(s): Mukoyama M, Ogawa Y, Yokoi H, Kasahara M, Mori K, Yoshioka T, Saito Y, Kuwabara T, Imamaki H, Kishimoto I, Sugawara A, Nakao K
  • Organizer: 2009年世界腎臓学会
  • Place of Presentation: ミラノ、イタリア
  • Year and Date: 2009-05-25
• [Presentation] Protective effect of atrial natriuretic peptide receptor guanylyl cyclase-A signaling on aldosteroneinduced renal injury. (2008)
  • Author(s): Ogawa Y, Mukoyama M, Yokoi H, Kasahara M, Mori K, Yoshioka T, Saito Y, Kuwabara T, Imamaki H, Sugawara A, Nakao K
  • Organizer: 第41回米国腎臓学会学術集会
  • Place of Presentation: フィラデルフィア、アメリカ
  • Year and Date: 2008-11-06
• [Presentation] Protective effect of atrial natriuretic peptide receptor guanylyl cyclase-A signaling on aldosterone-induced renal injury. (2008)
  • Author(s): Yoshihisa Ogawa, et al.
  • Organizer: 41st Annual Meeting of the American Society of Nephrology
  • Place of Presentation: 米国フィラデルフィア
  • Year and Date: 2008-11-06
• [Remarks] ホームページ等
  • URL: http://www.kuhp.kyoto-u.ac.jp/~med2/index-jp.html
• [Patent(Industrial Property Rights)] 腹膜癒着防止用医薬組成物 (2010)
  • Inventor(s): 中尾一和、横井秀基、向山政志、笠原正登、森潔、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 Number: 2010-051171
  • Filing Date: 2010-03-08