糖尿病性腎症治療ターゲットとしての核内受容体の研究

• 研究課題/領域番号: 21249053
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 腎臓内科学
• 研究機関: 岡山大学
• 研究代表者: 槇野 博史 岡山大学, 大学院・医歯薬学総合研究科, 教授 (50165685)
• 研究分担者: 和田 淳 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (30294408)
• 連携研究者: 小川 大輔 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (70535195)
• 研究期間 (年度): 2009 – 2012
• 研究課題ステータス: 完了 (2012年度)
• 配分額: 45,500千円 (直接経費: 35,000千円、間接経費: 10,500千円); 2012年度: 7,020千円 (直接経費: 5,400千円、間接経費: 1,620千円); 2011年度: 12,350千円 (直接経費: 9,500千円、間接経費: 2,850千円); 2010年度: 12,350千円 (直接経費: 9,500千円、間接経費: 2,850千円); 2009年度: 13,780千円 (直接経費: 10,600千円、間接経費: 3,180千円)
• キーワード: 核内受容体 / 糖尿病性腎症 / レチノイド / 細胞周期 / 糸球体上皮細胞 / PPAR / RXR / LXR

研究概要

糖尿病性腎症の病態の初期には細胞肥大が重要であり、その後慢性炎症が糖尿病性腎症の進展を促進させている。核内受容体のmodulatorはこれらの病態を総合的に改善する薬剤の候補である。Peroxisome proliferator-activated receptor (PPAR)-δアゴニストおよびLiver X receptor (LXR)アゴニストは抗炎症作用によって治療効果を発揮し、Retinoid X receptor (RXR)アンタゴニストは主として細胞周期の異常を是正して細胞肥大を抑制することが判明した。核内受容体のmodulatorは糖尿病性腎症に有効であると考えられる。

研究成果

• [雑誌論文] Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease (2013)
  • 著者名/発表者名: Kurose Y, Wada J, Kanzaki M, Teshigawara S, Nakatsuka A, Murakami K, Inoue K, Terami T, Katayama A, Watanabe M,Higushi C, Eguchi J, Miyatake N, Makino H
  • 雑誌名: BMC Nephrol 巻: 14 ページ: 23-23
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• [雑誌論文] Vaspin inhibits apoptosis of endothelial cells as a ligand for cell-surface GRP78/VDAC complex (2013)
  • 著者名/発表者名: Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Ogawa D, Matsuki Y, Hiramatsu R, Tagita H, Kakuta S, Iwakura Y, Makino H
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  • 査読あり
• [雑誌論文] Telmisartan attenuates diabetic nephropathy by suppressing ixidative stress in db/db mice (2013)
  • 著者名/発表者名: Sato-Horiguchi C, Ogawa D, Wada J, Tachibana H, Kodera R, Eguchi J, Nakatsuka A, Terami N, Shikata K, Makino H
  • 雑誌名: Nephron Exp Nephrol 巻: 121(3-4)
  • 査読あり
• [雑誌論文] The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO) (2013)
  • 著者名/発表者名: Murakami K, Wada J, Ogawa D, Horiguchi CS, Miyoshi T, Sasaki M, Uchida HA, Nakamura Y, Makino H
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  • 査読あり
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  • 雑誌名: Diab Vasc Dis Res 巻: 10(1) 号: 1 ページ: 93-96
  • DOI: 10.1177/1479164112444640
  • 査読あり
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  • 著者名/発表者名: Sato-Horiguchi C
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  • 査読あり
• [雑誌論文] Vaspin inhibits apoptosis of endothelial cells as a ligand for cell-surface GRP78/VDAC complex. (2013)
  • 著者名/発表者名: Nakatsuka A
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  • DOI: 10.1161/circresaha.111.300049
  • 査読あり
• [雑誌論文] Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease. (2013)
  • 著者名/発表者名: Kurose Y
  • 雑誌名: BMC Nephrol 巻: 14 号: 1 ページ: 23-23
  • DOI: 10.1186/1471-2369-14-23
  • 査読あり
• [雑誌論文] The serum vaspin levels are reduced in Japanese chronic hemodialysis patients. (2012)
  • 著者名/発表者名: Inoue J, Wada J, Teshigawara S, Hida K, Nakatsuka A, Takatori U, Kojo S, Akagi S, Nakao K, Miyatake N, McDonald JF, Makino H
  • 雑誌名: BMC Nephrol 巻: 13(1) ページ: 163-163
  • NAID: 120005315579
  • 査読あり
• [雑誌論文] Activation of liver x receptor inhibits osteopontin and ameliorates diabetic nephropathy (2012)
  • 著者名/発表者名: Tachibana H, Ogawa D, Matsushita Y,Bruemmer D, Wada J, Teshigawara S, Eguchi J, Sato-Horiguchi C, Uchida HA, Shikata K, Makino H
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  • 著者名/発表者名: Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Horiguchi CS, Ogawa D, Matsuki Y, Hiramatsu R, Yagita H, Kakuta S, Iwakura Y, Makino H
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  • 著者名/発表者名: Teshigawara S, Wada J, Hida K, Nakatsuka A, Eguchi J, Murakami K, Kanzaki M, Inoe K, Terami T, Katayama A, Iseda I, Matsushita Y, Miyatake N, McDonald JF, Hotta K, Makino H
  • 雑誌名: J Clin Endocrinol Metab 巻: 97(7)
  • NAID: 120005232486
  • 査読あり
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  • 著者名/発表者名: Kanzaki M, Wada J, Sugiyama K, Nakatsuka A, Teshigawara S, Murakami K, Inoue K, Terami T, Katayama A, Eguchi J, Akiba H, Yagita H, Makino H
  • 雑誌名: Endocrinology 巻: 153(2) ページ: 612-620
  • 査読あり
• [雑誌論文] Impact of circulating vaspin levels on metabolic variables in elderly twins (2012)
  • 著者名/発表者名: Hida K, Poulsen P, Teshigawara S, Nilsson E, Friedrichsen M, Ribel-Madsen R, Grunnet L, Lund SS, Wada J, Vaag A
  • 雑誌名: Diabetologia 巻: 55(2) ページ: 530-532
  • 査読あり
• [雑誌論文] RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21^Cip1pathway in adipocytes. (2012)
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  • 雑誌名: J Pathol 巻: 226(5) ページ: 784-795
  • NAID: 130004505771
  • 査読あり
• [雑誌論文] Impact of circulating vaspin levels on metabolic variables in elderly twins. (2012)
  • 著者名/発表者名: Hida K
  • 雑誌名: Diabetologia 巻: 55(2) 号: 2 ページ: 530-532
  • DOI: 10.1007/s00125-011-2385-0
  • 査読あり
• [雑誌論文] Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. (2012)
  • 著者名/発表者名: Kanzaki M
  • 雑誌名: Endocrinology 巻: 153(2) 号: 2 ページ: 612-620
  • DOI: 10.1210/en.2011-1579
  • 査読あり
• [雑誌論文] Serum vaspin concentrations are closely related to insulin resistance and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. (2012)
  • 著者名/発表者名: Teshigawara S
  • 雑誌名: J Clin Endocrinol Metab 巻: 97(7) 号: 7 ページ: E1202-E1207
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  • 査読あり
• [雑誌論文] Activation of liver x receptor inhibits osteopontin and ameliorates diabetic nephropathy. (2012)
  • 著者名/発表者名: Tachibana H
  • 雑誌名: J Am Soc Nephrol 巻: 23(11) 号: 11 ページ: 1835-1846
  • DOI: 10.1681/asn.2012010022
  • 査読あり
• [雑誌論文] The serum vaspin levels are reduced in Japanese chronic hemodialysis patients. (2012)
  • 著者名/発表者名: Inoue J
  • 雑誌名: BMC Nephrol 巻: 13(1) 号: 1 ページ: 163-163
  • DOI: 10.1186/1471-2369-13-163
  • 査読あり
• [雑誌論文] RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21Cip1 pathway in adipocytes (2012)
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  • 査読あり
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  • 雑誌名: Endocrinology 巻: 51(6) ページ: 619-623
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• [雑誌論文] High glucose increases metallothionein expression in renal proximal tubular epithelial cells. (2011)
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• [雑誌論文] Icodextrin increases technique survival rate in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management: a randomized controlled trial. (2011)
  • 著者名/発表者名: Takatori Y, Akagi S, Sugiyama H, Inoue J, Kojo S, Morinaga H, Nakao K, Wada J, Makino H
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• [雑誌論文] Activation of Peroxisome Proliferator-Activated Receptor δInhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice (2011)
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  • 雑誌名: Diabetes 巻: 60(3) ページ: 960-968
  • 査読あり
• [雑誌論文] P-selectin glycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance (2011)
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  • 査読あり
• [雑誌論文] Icodextrin increases technique survival rate in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management : a randomized controlled trial (2011)
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  • 雑誌名: Clin J Am Soc Nephrol 巻: 6 ページ: 1337-1344
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• [雑誌論文] High glucose increases metallothionein expression in renal proximal tubular epithelial cells (2011)
  • 著者名/発表者名: Ogawa D, et al
  • 雑誌名: Exp Diabetes Res 巻: 2011 ページ: 534872-534872
  • 査読あり
• [雑誌論文] In vivo delivery of gremlin siRNA plasmid reveals therapeutic potential against diabetic nephropathy by recovering bone morphogenetic protein-7. (2010)
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  • 査読あり
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  • 著者名/発表者名: Nakao A, Nakao K, Takatori Y, Kojo S, Inoue J, Akagi S, Sugiyama H, Wada J, Makino H
  • 雑誌名: Nephrol Dial Transplant 巻: 25(5) ページ: 1479-1488
  • 査読あり
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  • 査読あり
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  • NAID: 120002311418
  • 査読あり
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  • NAID: 120002383776
  • 査読あり
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  • 査読あり
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  • 雑誌名: Clin Immunol 巻: 136 ページ: 447-455
  • 査読あり
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  • 雑誌名: Biochim Biophys Acta 1802(2) ページ: 240-246
  • 査読あり
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  • 著者名/発表者名: Shikata K, Haneda M, Koya D, Suzukj Y, Tomino Y, Yamada K, Maeda S, Kawakami N, Uzu T, Nishimura M, Sato C, Ogawa D, Makino H ; DNETT-Japan Study Group
  • 雑誌名: Diabetes Res Clin Pract 87(2) ページ: 228-232
  • 査読あり
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  • 雑誌名: Am J Physiol Cell Physiol 巻: 297(4)
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• [雑誌論文] Olmesartan and Temocapril Prevented the Development of Hyperglycemia and the Deterioration of Pancreatic Islet Morphology in Otsuka-Long-Evans-Tokushima Fatty Rats (2009)
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  • NAID: 120002313118
  • 査読あり
• [雑誌論文] Urinary excretions of lipocalin-type prostaglandin D synthase predict renal injury in type-2 diabetes : a cross-sectional and prospective multicentre study (2009)
  • 著者名/発表者名: Makino H, Uehara Y, Seiki K, Urada Y on behalf of L-PGDS Clinical Research Group of Kidney
  • 雑誌名: Nephrol Dial Transplant 24 ページ: 475-482
  • 査読あり
• [雑誌論文] Long-term effect of modification of dietary protein intake on the progression of diabetic nephropathy : a randomized controlled trial (2009)
  • 著者名/発表者名: Koya D, Haneda M, Inomata S, Suzuki J, Suzuki D, Makino H, Shikata K, Murakami Y, Tomino Y, Yamada K, Araki S, Kashiwagi Y, Kikkawa R on behalf of the Low-Protein Diet Study Group
  • 雑誌名: Diabetologia 52 ページ: 2037-2045
  • 査読あり
• [雑誌論文] Beta-Blocker Prescription and Outcomes in Hemodialysis Patients from The Japan Dialysis Outcomes and Practice Patterns Study. (2009)
  • 著者名/発表者名: Nakao K, Makino H, Morita S, Takahashi Y, Akizawa T, Saito A, Asano Y, Kurokawa K, Fukuhara S, Akiba T, for the JDOPPS investigators group
  • 雑誌名: Nephron Clin Pract 113(3)
  • 査読あり
• [雑誌論文] Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mousemodel of diabetic nephropathy (2009)
  • 著者名/発表者名: Nasu T, Maeshima Y, Kinomura M, Hirokoshi-Kawahara K, Tanabe K, Sugiyama H, Sonoda H, Sato Y, Makino H
  • 雑誌名: Diabetes 58(10) ページ: 2365-2375
  • 査読あり
• [雑誌論文] Clinical usefulness of a prognostic score in histological analysis of renal biopsy in patients with lupus nephritis (2009)
  • 著者名/発表者名: Kojo S, Sada KE, Kobayashi M, Maruyama M, Maeshima Y, Sugiyama H, Makino H
  • 雑誌名: J Rheumatol 36(10) ページ: 2218-2223
  • 査読あり
• [雑誌論文] Effects of icodextrin peritoneal dialysis solution on the peritoneal membrane in the STZ-induced diabetic rat model with partial nephrectomy (2009)
  • 著者名/発表者名: Nakao A, Nakao K, Takatori Y, Kojo S, Inoue J, Akagi S, Sugiyama H, Wada J, Makino H
  • 雑誌名: Nephrol Dial Transplant (In press)
  • 査読あり
• [雑誌論文] Urinary excretions of lipocalin-type prostaglandin D synthase predict renal injury in type-2 diabetes : a cross-sectional and prospective multicentre study. (2009)
  • 著者名/発表者名: Uehara Y, Makino H, Seiki K, Urade Y, LPGDS Clinical Research Group of Kidney
  • 雑誌名: Nephrol Dial Transplant 24(2) ページ: 475-482
  • 査読あり
• [雑誌論文] Endothelial barrier protection by FTY720 under hyperglycemic condition : involvement of focal adhesionkinase, small GTPases, and adherens function proteins. (2009)
  • 著者名/発表者名: Sarai K, Shikata K, Shikata Y, Omori K, Watanabe N, Sasaki M, Nishishita S, Wada J, Goda N, Kataoka N, Makino H
  • 雑誌名: Am J Physiol Cell Physiol 297(4)
  • 査読あり
• [学会発表] Renin angiotensin system inhibition in diabetic nephropathy. (2012)
  • 著者名/発表者名: Makino H:
  • 学会等名: ASN Kidney Week 2012
  • 発表場所: San Diego, CA, USA
  • 年月日: 2012-11-02
• [学会発表] Basic mechanism underlying diabetic nephropathy and CKD. (2011)
  • 著者名/発表者名: Makino H:
  • 学会等名: World Congress of Nephrology
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-11
• [学会発表] Basic Mechanisms Underlying Diabetic Nephropathy and CKD (2011)
  • 著者名/発表者名: Hirofumi Makino
  • 学会等名: World Congress of Nephrology
  • 発表場所: Vancouver, Canada
  • 年月日: 2011-04-11
• [学会発表] 全身を制御する腎臓-33年の腎臓研究を顧みて- (2010)
  • 著者名/発表者名: 槇野博史
  • 発表場所: 神戸市
  • 年月日: 2010-06-17
• [学会発表] 全身を制御する腎臓-33年の腎臓研究を顧みて- (2010)
  • 著者名/発表者名: 槇野博史
  • 学会等名: 第53回日本腎臓学会学術総会
  • 発表場所: 神戸ポートピアホテル(神戸市)(会長講演)
  • 年月日: 2010-06-17
• [学会発表] Thiazolidinediones and diabetic nephropathy (2009)
  • 著者名/発表者名: Makino H
  • 学会等名: World Congress of Nephrology
  • 発表場所: Milan, Italy
  • 年月日: 2009-05-22
• [学会発表] Thiazolidiones and diabetic kidney disease (2009)
  • 著者名/発表者名: Makino H
  • 学会等名: World Congress of Nephrology
  • 発表場所: Milan, Italy
  • 年月日: 2009-05-22
• [学会発表] Renin angiotensin system inhibition in diabetic nephropathy.
  • 著者名/発表者名: Makino H
  • 学会等名: ASN Kidney Week 2012
  • 発表場所: San Diego, CA, USA
  • 招待講演
• [図書] 糖尿病×CKD診療ガイド (2012)
  • 著者名/発表者名: 槇野博史
  • 総ページ数: 197
  • 出版者: 南山堂
• [図書] CKDのサイエンス-基礎と臨床- (2010)
  • 著者名/発表者名: 槇野博史編
  • 総ページ数: 230
  • 出版者: 南山堂