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Pathophysiological Roles of Peroxisome Proliferator Activated Receptor (PPAR) on Development and Progression of Chronic kidney diseases -Search for a New Therapeutic Target for Chronic Kidney Diseases-

Research Project

Project/Area Number 13470212
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionFukushima Medical University

Principal Investigator

WATANABE Tsuyoshi  Fukushima Medical University, School of Medicine, Professor, 医学部, 教授 (80158641)

Co-Investigator(Kenkyū-buntansha) KATOH Tetsuo  Fukushima Medical University, School of Medicine, Lecturer, 医学部, 講師 (70194834)
SANADA Hironobu  Fukushima Medical University, School of Medicine, Lecturer, 医学部, 講師 (40254007)
ASAHI Kouichi  Fukushima Medical University, School of Medicine, Assistant, 医学部, 助手 (60274966)
TSUKAMOTO Kazuhisa  University of Tokyo, School of Medicine, Assistant, 医学部, 助手 (20251233)
馬場 恒春  福島県立医科大学, 医学部, 講師 (60183571)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2002: ¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2001: ¥6,700,000 (Direct Cost: ¥6,700,000)
KeywordsPPAR / diabetic nephropathy / VEGF / IgA nephropathy / poly-unsaturated fatty acid (PUFA) / thiazolizinedione / inflammation / prostanoids / 慢性腎不全 / インスリン抵抗性 / アデノウィルス・ベクター / 脂肪酸 / thiazolidinedione / fibrate / アデノウイルス・ベクター / thiazolidina
Research Abstract

(1)Pathogenetic actions of Peroxisome Proliferator Activated Receptor (PPAR) on glomerular cells: In rat mesangial cells in culture, high ambient glucose(25mM), especially when fluctuated time by time, promoted Vascular Endothelial Growth Factor(VEGF) production and DNA synthesis, which is inhibited by treatment of the cells with a thiazolizinedione, a PPAR, agonist. In the kidney specimens from 18 type 2 patients with early stage of diabetic nephropathy, glomerular VEGF messenger RNA expression determined by in situ hybridization is well correlated with neovasculization at the vascular pole and mesangial matrix area^<1)> (glomerular sclerosis) ^<6)>. We presented a case of POEMS (Crow-Fukase) syndrome with Type 2 diabetes, which was associated with elevated plasma VEGF level, but no sign of diabetic nephropathy^<8)>. We also measured plasma VEGF concentration in Type 2 diabetic patients with normo-, micro, and macro-albuminuria, the results of which showed that the presence of DN is n … More ot associated with an elevation of circulating plasma VEGF concentration2). These results suggest that overproduction of VEGF in situ in the kidney may play a local pathogenetic role in early-stage DN, which is dependent on PPAR,and PKC.
(2)Establishment of gene transfer system using adenovirus vector and application for model animals with renal diseases : We established a system of mRNA measurement by RT-real time PCR(light-cycler) and that of gene transfer system using adeno-virus vector encoding PPAR,, and PAF-AH cDNA (AdhPPAR,,nd AdhPAF-AH) which are confirmed to express respective mRNA and protein in various culture cell systems.First, AdhPAF-AH was trasfected to a nephrosclerosis model animal (SHC rat), which resultantly inhibited nephrosclerosis through PAF-AH expression in the liver and transferred to the kidney on HDL particles12). Estabulishment of kidney specific, effective gene transfer system would promote application of AdhPPAR,、,nd AdhPAF-AH for gene therapy of various model animals for common renal disease such as diabetic nephropathy or IgA nephropathy.
(3)Pathogenetic roles of PPAR and its related factors for the pathophysiology in animal models with renal diseases: IgA nephropathy model mice (HIGA mouse) were feeded with,inolenic acid (an, 3 series poly-unsaturated fatty acid (PUFA))-or linolic acid (, 6 series PUFA) which are also possible ligands for PPAR. Feeding with,inolenic acid compared to that with linolic acid inhibited proteinuria, renal dysfunction(increase in plasma creatinine) and glomerular sclerotic change^<13)>, suggesting a potential involvement in pathogenesis and a potential therapeutic target of PPAR for IgA nephropathy. The physiological roles of prostanoids (PUFA-derived autacoid) in the kidney are tested using their receptor knoch-out mce, suggesting that salt-sensitivity is partly dependent upon prostanoids^<10)>, but ischemic acute renal failure^<3)>. In additon, direct micro-dilution into the remnant kidney in unilateral nephrectomizen, salt-loaded rats of an anti-sense oligonucleotide to type 1 angiotensin II receptor(AT1) amelionate proteinuria and patho-histological changes without changing blood pressure in spontaneous hypertensive rats (SHR) ^<11)>, supporting the concept that angiotensin II locally produced plays a significant roles in progression of renal dysfunction via ATI receptor signals.
(4)Clinical studies targeted for cardio-vascular events in chronic kidney diseases : We registered about 600 HD patients and cross-sectionally examined the clinical parameters responsible for incidence of cardiovascular, which showed that the strongest predictor for events is inflammation (CRP) followed by diabetes and so forth and that use of ARB and/or ACE inhibitors inaddition of BW, serum albumin and body weight representative for good nutritional state and effectiveness of hemodialysis (HD) (Kt/V) improved life prognosis^<5)>. Intake of, inolenic acid improved CRP in the control population, but not in the HD patients (manuscript in preparation), explaining partly poor prognosis due to cardiovascular events of HD patients. Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (40 results)

All 2006 2005 2004 2003 2002 Other

All Journal Article (21 results) Publications (19 results)

  • [Journal Article] Adenovirous-mediated gene transfer and lipoprotein-mediated protein delivery of plasma PAF-AH ameliorates proteinuria in rat model of glomerulosclerosis.2006

    • Author(s)
      Iso-o N
    • Journal Title

      Mol.Ther. 13(1)

      Pages: 118-126

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Adenovirous-mediated gene transfer and lipoprotein-mediated protein delivery of plasma PAF-AH ameliorates proteinuria in rat model of glomerulosclerosis.2006

    • Author(s)
      Iso-o Naoyuki
    • Journal Title

      Mol.Ther. 13(1)

      Pages: 118-126

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy.2005

    • Author(s)
      Yoshinobu Kanesaki
    • Journal Title

      Am.J.Kid.Dis. 45(2)

      Pages: 288-294

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effects of salt loading on the blood pressure in mice lacking prostanoid receptor gene.2005

    • Author(s)
      Hidetuna Watanabe
    • Journal Title

      Circ.J. 69(1)

      Pages: 124-126

    • NAID

      110002696056

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Differential effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneous hypertensive rats.2005

    • Author(s)
      Minoru Yoneda
    • Journal Title

      Hypertension 46

      Pages: 58-65

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] 植物性n-3不飽和脂肪酸(PUFA)によるHIGAマウスにおけるIgA腎症抑制効果2005

    • Author(s)
      桜井薫
    • Journal Title

      日本腎臓学会誌(ポスター発表 : 英文にて論文作成中) 47(3)

      Pages: 303-303

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy.2005

    • Author(s)
      Yoshinobu Kanesaki
    • Journal Title

      Am.J.Kidney.Dis. 45(2)

      Pages: 288-294

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Effects of salt loading on the blood pressure in mice lacking prostanoid receptor gene.2005

    • Author(s)
      Hidetsuna Watanabe
    • Journal Title

      Circ.J. 69(1)

      Pages: 124-126

    • NAID

      110002696056

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Rapid change of glucose concentration promotes mesangial cell proliferation via VEGF : Inhibitory effects of thiazolidinedione2004

    • Author(s)
      Akira Onozaki
    • Journal Title

      Biochem.Biophys.Res.Commun. 317

      Pages: 24-29

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Close relationship of plasminogen activator inhibitor-1 4G/5> polymorphism and progression of IgA nephropathy.2004

    • Author(s)
      Hodaka Suzuki
    • Journal Title

      Clin.Nephrol. 62(3)

      Pages: 173-179

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] No nephropathy in type 2 diabetic patient with POEMS syndrome with an elevatedd plasma VEGF.2004

    • Author(s)
      Tuneharu Bada
    • Journal Title

      Diabet.Med. 21(3)

      Pages: 292-294

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] No nephropathy in type 2 diabetic patient with POEMS syndrome with an elevatedd plasma VEGF.2004

    • Author(s)
      Tsuneharu Baba
    • Journal Title

      Diabet.Med. 21(3)

      Pages: 292-294

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Insulin resistance highly associates with hypertension in IgA nephropathy.2003

    • Author(s)
      Masaaki Eiro
    • Journal Title

      Clin.Nephrol. 59(2)

      Pages: 71-78

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] The Effect of Renin-Angiotensin System (RAS) Blockade on Mortality of Chronic Hemodialysis(HD)Patients.2003

    • Author(s)
      Koichi Asahi
    • Journal Title

      Am.Soc.Nephrol. 14

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] The Effect of Renin-Angiotensin System (RAS) Blockade on Mortality of Chronic Hemodialysis (HD) Patients2003

    • Author(s)
      Koichi Asahi
    • Journal Title

      Am.Soc.Nephrol. 14

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] The product of the duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointestinal damage in IgA nephropathy.2002

    • Author(s)
      Masaaki Eiro
    • Journal Title

      Nephron 90(4)

      Pages: 432-441

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Plasma vascular endothelial growth factor in Japanese type 2 diabetic patients with and without nephropathy2002

    • Author(s)
      Kouichi Shimada
    • Journal Title

      J.Diabetes & Its Complication 16

      Pages: 386-390

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Lack of prostanoid receptor involvement in ishemic acute renal failure in mice.2002

    • Author(s)
      Masaaki Eiro
    • Journal Title

      Clin.Exp.Nephrol. 6(2)

      Pages: 85-90

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Plasma vascular endothelial growth factor in Japanese type 2 diabetic patients with and without nephropathy ;2002

    • Author(s)
      Kouichi Shimada
    • Journal Title

      J.Diabetes & Its Complications 16(2)

      Pages: 386-390

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Lack of prostanoid receptor involvement in ishemic acute renal failure in mice.2002

    • Author(s)
      Masaaki Eiro
    • Journal Title

      Clin.Exp.Nephrol. 6

      Pages: 85-90

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Preventive Effect of vegetable n-3 poly-unsaturated fatty acid (PUFA) on development of IgA nephropathy in HIGA mice, a model animal for spontaneous IgA nephropathy.

    • Author(s)
      Kaoru Sakurai
    • Journal Title

      Jap.J.Nephrol.(in Japanese) 47(3)

      Pages: 303-391

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] S.Neubebauer: "Total plasma homocysteine is associated with hypertension in type I diabetic patients."Diabetologia. 45. 1315-1324 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Masaaki Eiro: "Insulin resistance highly associates with hypertension in IgA nephropathy."Clin.Nephrol.. 59(2). 71-78 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Minoru Kuriki: "Steroid therapy regresses mesangial matrix accumulation in advanced IgA nephropathy."Nephrol.Dial.Transplant.. 18. 1311-1315 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tsuneharu Baba: "No nephropathy in type 2 diabetic patient with POEMS syndrome with an elevatedd plasma VEGF."Diabetic Medicine. 21(3). 292-294 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Akira Onozaki: "Rapid change of glucose concentration promotes mesangial cell proliferation via VEGF : Inhibitory effects of thiazolidinedione"Biochem.Biophys.Res.Commun.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hodaka Suzuki: "Close relationship of plasminogen activator inhibitor-1 4G/5> polymorphism and progression of IgA nephropathy."Clin.Nephrol.. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] T.Gohda: "Association of the DD genotype and development of Japanese type 2 diabetic nephropathy"Clin. Nephrol.. 56. 475-480 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masaaki Eiro: "The product of the duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointestinal damage in IgA nephropathy"Nephron.. 90. 432-441 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masaaki Eiro: "Use of a proton-pump inhibitor for metabolic disturbances associated with anorexia nervosa"N. Eng. J. Med.. 346. 140 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kouichi Shimada: "Plasma vascular endothelial growth factor in Japanese type 2 diabetic patients with and without nephropathy"J. Diabetes & Its Complications. 16. 386-390 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] S.Neubebauer: "Total plasma homocysteine is associated with hypertension in type I diabetic patients"Diabetologia.. 45. 1315-1324 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Masaaki Eiro: "Insulin resistance highly associates with hypertension in IgA nephropathy"Chin. Neplirol.. 59 (2). 71-78 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tsuyoshi Watanabe: "Laboratory Techniques in Renal Cell and Molecular Biology. 分担 (Western Blot Method)"KARGER. 11 (2000)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ken Katoh: "Improvement by an insulin-sensitizing drug, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus"Metabolism. 49. 662-665 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tsuneharu Baba: "Oral insulin sensitizer, thiazolidinedione, increase plasma VEGF in type 2 diabetic patients"Diabetes Care. 24. 953-954 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Masaaki Eiro: "The product of the duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointestinal damage in IgA nephropathy"Nephron. (in press). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Gohda: "Association of the DD genotype and development of Japanese type 2 diabetic nephropathy"Clin. Nephrol. 56. 475-480 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Akira Onozaki: "Congenital nephrogenic diabetes insipidus with marked hyponatremia"Clin.Exp.Nephrol. 5. 265-267 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hodaka Suzuki: "Recovery from renal failure in malignant hypertension associated with primaryaldosteronism : Effect of ACE inhibitor"QJM. (in press). (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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