Development of the novel therapeutic strategy for diabetic nephropathy through anti-inflammatory effects.

• Project/Area Number: 21591031
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Okayama University
• Principal Investigator: SHIKATA Kenichi 岡山大学, 岡山大学病院, 教授 (00243452)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腎臓病学 / 糖尿病性腎症 / microinflammation / osteopontin / cholecystokinin / 炎症 / 糖尿病 / マクロファージ / Cholecystokinin / Osteopontin

Research Abstract

We have demonstrated that low grade inflammation, microinflammation, is involved in the pathogenesis of diabetic nephropathy as well as of atherosclerosis. We have recently reported that anti-inflammatory agents such as statin and thiazolidinedione show renoprotective effects through anti-inflammatory actions in diabetic animals. In this study, 1) We induced diabetes into osteopontin knockout(KO) mice. Osteopontin KO mice showed the improvement of tissue injuries and inflammatory reactions in the kidney. 2) We found that GLP-1 receptor is expressed on monocte/macrophage and glomerular endothelial cells. GLP-1 receptor agonist showed renoprotective effects on diabetic rats through anti-inflammatory actions. These results suggest that osteopontin play a role in the pathogenesis of diabetic nephropathy and GLP-1 receptor agonist might be beneficial for the treatment of diabetic nephropathy.

Research Products

• [Journal Article] Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage : anti-inflammatory effect of cholecystokinin (2012)
  • Author(s): Miyamoto S, Shikata K, Miyasaka K, Okada S, Sasaki M, Kodera R, Hirota D, Kajitani N, Takatsuka T, Kataoka HU, Nishishita S, Sato C, Funakoshi A, Nishimori H, Uchida HA, Ogawa D, Makino H
  • Journal Title: Diabetes Volume: 61 Pages: 897-907
  • NAID: 40019575963
  • Peer Reviewed
• [Journal Article] High glucose increases metallothionein expression in renal proximal tubular epithelial cells (2012)
  • Author(s): Ogawa D, Asanuma M, Miyazaki I, Tachibana H, Wada J, Sogawa N, Sugaya T, Kitamura S, Maeshima Y, Shikata K, Makino H
  • Journal Title: Exp Diabetes Res Pages: 534872-534872
  • Peer Reviewed
• [Journal Article] Phenotypic change of macrophages in the progression of diabetic nephropathy ; sialoadhesin-positive activated macrophages are increased in diabetic kidney (2012)
  • Author(s): 永瀬亮
  • Journal Title: Clin Exp Nephrol Volume: (in press)
  • Peer Reviewed
• [Journal Article] Cholecystokinin plays a novel protective role in diabetic kidney through anti-inflammatory actions on macrophage. -anti-inflammatory effect of CCK- (2012)
  • Author(s): 宮本聡
  • Journal Title: Diabetes Volume: (in press)
  • Peer Reviewed
• [Journal Article] Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice (2011)
  • Author(s): Matsushita Y, Ogawa D, Wada J, Yamamoto N, Shikata K, Sato C, Tachibana H, Toyota N, Makino H
  • Journal Title: Diabetes Volume: 60 Pages: 960-968
  • Peer Reviewed
• [Journal Article] Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes (2011)
  • Author(s): Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, Kajitani N, Nishishita S, Sarai K, Hirota D, Sato C, Ogawa D, Makino H
  • Journal Title: Diabetologia Volume: 54 Pages: 965-978
  • Peer Reviewed
• [Journal Article] (2011)
  • Author(s): Sato C, Shikata K, Hirota D, Sasaki M, Nishishita S, Miyamoto S, Kodera R, Ogawa D, Tone A, Kataoka HU, Wada J, Kajitani N, Makino H
  • Journal Title: Diabetes Volume: 60 Pages: 189-199
  • Peer Reviewed
• [Journal Article] Intercellular adhesion molecule-1 plays a critical role in glomerulosclerosis after subtotal nephrectomy (2011)
  • Author(s): Kido Y, Ogawa D, Shikata K, Sasaki M, Nagase R, Okada S, Usui Kataoka HU, Wada J, Makino H
  • Journal Title: Clin Exp Nephrol Volume: 15 Pages: 212-219
  • NAID: 10029005164
  • Peer Reviewed
• [Journal Article] Renoprotective effects of clarithromycin via reduction of urinary MCP-1 levels in type 2 diabetic patients (2011)
  • Author(s): Tone A, Shikata K, Nakagawa K, Hashimoto M, Makino H
  • Journal Title: Clin Exp Nephrol Volume: 15 Pages: 79-85
  • NAID: 10029004515
  • Peer Reviewed
• [Journal Article] Comparison of insulin detemir and insulin glargine on glycemic variability in patients with type 1 and type 2 diabetes (2011)
  • Author(s): Tone A, Iseda I, Higuchi C, Tsukamoto K, Katayama A, Matsushita Y, Hida K, Wada J, Shikata K
  • Journal Title: Exp Clin Endocrinol Diabetes Volume: 118 Pages: 320-324
  • Peer Reviewed
• [Journal Article] The Relation between estimated glomerular filtration rate(eGFR) and proteinuria in Okayama prefecture, Japan (2011)
  • Author(s): Miyatake N, Shikata K, Makino H, Numata T
  • Journal Title: Environ Health Prev Med Volume: 16 Pages: 191-195
  • Peer Reviewed
• [Journal Article] Comparison of ventilatory threshold between subjects with and without proteinuria in Japanese (2011)
  • Author(s): Miyatake N, Shikata K, Makino H, Numata T
  • Journal Title: Health Volume: 3 Pages: 394-399
  • Peer Reviewed
• [Journal Article] Decreasing serum uric acid levels might be associated with improving estimated glomerular filtration rate(eGFR) in Japanese men (2011)
  • Author(s): Miyatake N, Shikata K, Makno H, Numata T
  • Journal Title: Health Volume: 3 Pages: 498-503
  • Peer Reviewed
• [Journal Article] The relation between estimated glomerular filtration rate(eGFR) and coffee consumption in the Japanese (2011)
  • Author(s): Miyatake N, Shikata K, Makino H, Numata T
  • Journal Title: Health Volume: 3 Pages: 549-552
  • Peer Reviewed
• [Journal Article] Comparison of muscle strength between subjects with and without proteinuria (2011)
  • Author(s): Miyatake N, Shikata K, Makino H, Numata T
  • Journal Title: Health Volume: 3 Pages: 698-702
  • Peer Reviewed
• [Journal Article] High glucose increases metallothionein expression in renal proximal tubular epithelial cells (2011)
  • Author(s): 小川大輔
  • Journal Title: Exp Diabetes Res Volume: 534,872
  • Peer Reviewed
• [Journal Article] Involvement of MAPKs in ICAM-1 expression in glomerular endothelial cells in diabetic nephropathy (2011)
  • Author(s): 渡辺直美
  • Journal Title: Acta Med Okayama Volume: 65 Pages: 247-257
  • Peer Reviewed
• [Journal Article] The macrophage is a key factor in renal injuries caused by glomerular hyperfiltration (2011)
  • Author(s): 佐々木基史
  • Journal Title: Acta Med Okayama Volume: 65 Pages: 81-89
  • Peer Reviewed
• [Journal Article] The relation between estimated glomerular filtration rate and proteinuria in Okayama Prefecture, Japan (2011)
  • Author(s): 宮武伸行
  • Journal Title: Environ Health Prev Med Volume: 16
  • Peer Reviewed
• [Journal Article] P-selectin giycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance (2011)
  • Author(s): 佐藤千景
  • Journal Title: Diabetes Volume: 60 Pages: 189-199
  • Peer Reviewed
• [Journal Article] Activation of peroxisome proliferator-activated receptor delta inhibits streptozotocin-induced diabetic nephropathy through anti-inflammatory mechanisms in mice. (2011)
  • Author(s): Matsushita Y, Ogawa D, Wada J, Yamamoto N, Shikata K, Sato C, Tachibana H, Toyota N, Makino H.
  • Journal Title: Diabetes Volume: 60 Pages: 950-958
  • Peer Reviewed
• [Journal Article] Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. (2011)
  • Author(s): Kodera R, Shikata K, Kataoka HU, Takatsuka T, Miyamoto S, Sasaki M, Kajitani N, Nishishita S, Sarai K, Hirota D, Sato C, Ogawa D, Makino H.
  • Journal Title: Diabetologia Volume: 54 Pages: 965-978
  • Peer Reviewed
• [Journal Article] DNETT-Japan Study Group. Diabetic Nephropathy Remission and Regression Team Trial in Japan(DNETT-Japan): Rationale and study design (2010)
  • Author(s): Shikata K, Haneda M, Koya D, Suzuki Y, Tomino Y, Yamada K, Maeda S, Kawakami N, Uzu T, Nishimura M, Sato C, Ogawa D, Makino H
  • Journal Title: Diabetes Res Clin Pract Volume: 87(2) Pages: 228-232
  • Peer Reviewed
• [Journal Article] Relation between estimated glomerular filtration rate and pulse wave velocity in Japanese (2010)
  • Author(s): Miyatake N, Shikata K, Makino H, Numata T
  • Journal Title: Intern Med Volume: 49 Pages: 1315-1320
  • NAID: 130000299533
  • Peer Reviewed
• [Journal Article] Microinflammation is a common risk factor for progression of nephropathy and atherosclerosis in Japanese patients with type 2 diabetes (2010)
  • Author(s): Kajitani N, Shikata K, Nakamura A, Nakatou T, Hiramatsu M, Makino H
  • Journal Title: Diabetes Res Clin Pract Volume: 88 Pages: 171-176
  • Peer Reviewed
• [Journal Article] Relationship between estimated glomerular filtration rate (eGFR) and metabolic syndrome in Japanese. (2010)
  • Author(s): Miyatake N, Shikata K, Makino H, Numata T
  • Journal Title: Acta Mad Okayama Volume: 84 Pages: 202-208
  • NAID: 120002311048
  • Peer Reviewed
• [Journal Article] Diabetic Nephropathy Remission and Regression Team Trial in Japan(DNETT-Japan) : Rationale and study design. (2010)
  • Author(s): Shikata K, Haneda M, Koya D, Suzuki Y, Tomino Y, Yamada K, Maeda S, Kawakami N, Uzu T, Nishimura M, Sato C, Oqawa D.
  • Journal Title: Diabetes Res Clin Pract. 87 Pages: 228-232
  • Peer Reviewed
• [Journal Article] Low-Protein Diet Study Group. Long-term effect of modification of dietary protein intake on the p progression of diabetic nephropathy : a randomised controlled trial (2009)
  • Author(s): Koya D, Haneda M, Inomata S, Suzuki Y, Suzuki D, Makino H, Shikata K, Murakami Y, Tomino Y, Yamada K, Araki SI, Kashiwagi A, Kikkawa R
  • Journal Title: Diabetologia Volume: 52 Pages: 2037-2045
  • Peer Reviewed
• [Journal Article] Endothelial barrier protection of FTY720 under hyperglycemic condition : Involvement of focal adhesion kinase, small GTPases and adherens junction proteins (2009)
  • Author(s): Sarai K, Shikata K, Shikata Y, Omori K, Watanabe N, Sasaki M, Nishishita S, Wada J, Goda N, Kataoka N, Makino H
  • Journal Title: Am J Physiol Cell Physiol
  • Peer Reviewed
• [Journal Article] Endothelial barrier protection by FTY720 under hyperglycemic condition : involvement of focal adhesion kinase, small GTPases, and adherens junction proteins. (2009)
  • Author(s): Sarai K, Shikata K, Shikata Y, Omori K, Watanabe N, Sasaki M, Nishishita S, Wada J, Goda N, Kataoka N, Makino H.
  • Journal Title: Am J Physiol Cell Physiol. 297
  • Peer Reviewed
• [Journal Article] Advanced glycation end products subspecies-selectively induce adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells. (2009)
  • Author(s): Takahashi HK, Mori S, Wake H, Liu K, Yoshino T, Ohashi K, Tanaka N, Shikata K, Makino H, Nishibori M
  • Journal Title: J Pharmacol Exp Ther. 330 Pages: 89-98
  • Peer Reviewed
• [Journal Article] Phenotypic change of macrophages in the progression of diabetic nephropathy ; sialoadhesin-positive activated macrophages are increased in diabetic kidney
  • Author(s): Nagase R, Kajitani N, Shikata K, Ogawa D, Kodera R, Okada S, Kido Y, Makino H
  • Journal Title: Clin Exp Nephrol Volume: (In press)
  • NAID: 10031122261
  • Peer Reviewed
• [Presentation] 糖尿病性腎症の治療における新しい展開～Microinflammmationを標的とした治療戦略～ (2011)
  • Author(s): 四方賢一
  • Organizer: 第34回日本高血圧学会総会
  • Place of Presentation: 宇都宮市
  • Year and Date: 2011-10-21
• [Presentation] 糖尿病性腎症治療の最前線 (2011)
  • Author(s): 四方賢一
  • Organizer: 第26回糖尿病合併症学会
  • Place of Presentation: 大宮市
  • Year and Date: 2011-10-14
• [Presentation] 糖尿病性腎症の治療における新しい展開～MIcroinflammationを標的とした治療戦略～ (2011)
  • Author(s): 四方賢一
  • Organizer: 第75回日本循環器学会
  • Place of Presentation: 横浜市
  • Year and Date: 2011-08-03
• [Presentation] Telmisartan attenuates diabetic nephropathy through anti-oxidative and anti-inflammatory actions via activation of peroxisome proliferator-activated recep tor-γ (2011)
  • Author(s): Kajitani N, Shikata K, Kodera R, Miyamoto S, Hirota D, Sato C, Wada J, Ogawa D, and Makino H
  • Organizer: 47th AnnualMeeting of the European Ass ociation for the Study of Diabetes Lisbon Portugal
• [Presentation] Activation of Peroxisome Proliferator-activated ReceptorδInhibits Streptozotocin-induced Diabetic Nephropathy Through Anti-inflammatory Mechanisms in Mice (2011)
  • Author(s): Tachibana H, Ogawa D, Matsushita Y, Yamamoto N, Toyota N, Sato C, Wada J, Shikata K, Makino H
  • Organizer: American Diabetes Association 71st Scientific Sessions
  • Place of Presentation: San Diego, California, USA
• [Presentation] Activation of Peroxisome Proliferator-activated ReceptorδInhibits Streptozotocin-induced Diabetic Nephropathy Through Anti-inflammatory Mechanisms in Mice (2011)
  • Author(s): Ogawa D, Wada J, Matsushita Y, NakatsukaA, Murakami K, Kanzaki M, Shikata K, Makino H
  • Organizer: Keystone Symposia
  • Place of Presentation: Keystone, Colorado, USA
• [Presentation] PPARδ-mediated anti-inflammatory mechanisms inhibit streptozotocin-induced diabeticnephropathy (2010)
  • Author(s): Ogawa D, Matsushita Y, Shikata K, Wada J, Sato C, Makino H
  • Organizer: The 2nd Scientific Meeting of the Asian Association for the Study of Diabetes
  • Year and Date: 2010-05-29
• [Presentation] 糖尿病性腎症の成因としてのMicroinflammation (2010)
  • Author(s): 四方賢一
  • Organizer: 第53回日本糖尿病学会
  • Place of Presentation: ホテルグランヴィア岡山
  • Year and Date: 2010-05-28
• [Presentation] Exendin-4a meliorates renal injuries through an ti-oxidative and anti-inflammatory ef fectsin type 1 diabetic rats (2010)
  • Author(s): Kodera. R, Kataoka H, Shikata K, Sato C, Sasa ki M, Nishishita S, Miyamoto S, Hirota D, Kajitani N, Ogawa O, Makino H
  • Organizer: 46th EASD Annualmeeting Stocholm
  • Place of Presentation: Sweden
• [Presentation] PPARδ-mediated anti-inflammat orymechanisms inhibit streptozotocin-i nduceddiabetic nephropathy (2010)
  • Author(s): Ogawa D, Matsushita Y, Shikata K, Wada J, Sato C, Makino H
  • Organizer: ISN-NEXUS K yoto in 2010
  • Place of Presentation: Kyoto
• [Presentation] PPARδ-mediated anti-inflammatory mechanisms inhibit streptozotoci n-induced diabetic nephropathy (2010)
  • Author(s): Ogawa D, Matsushita Y, Shikata K, Wada J, Sato C, Makino H
  • Organizer: Keyston e Symposia
  • Place of Presentation: Banff, Alberta, Canada
• [Presentation] 糖尿病とCKD～管理の面から～チーム医療による集約的治療の意義 (2009)
  • Author(s): 四方賢一
  • Organizer: 第52回日本糖尿病学会年次学術集会 ジョイントシンポジウム4
  • Place of Presentation: 大阪
  • Year and Date: 2009-05-24
• [Presentation] Cholecystokinin amelioratesdia betic renal injuries via anti-inflam matory effects (2009)
  • Author(s): Miyamoto S Shikata K Sasaki M Nishishita S Sato C Kataoka H Kodera R Hirota D Kajitani N Makino H
  • Organizer: 45th EASD Annual Meeting
• [Presentation] Exendin-4 ameliorates renalinjuries through anti-oxidative a nd anti-inflammatory effects in type 1 d iabetic rats (2009)
  • Author(s): Kodera R, Kataoka H, Shikata K, Sato C, Sasaki M, Nishishita S, Miyamoto S, Hirota D, Kajitani N, Ogawa D, Makino H
  • Organizer: 45th EASD Annual meeting
• [Presentation] Exendin-4 ameliorates renalinjuries through anti-inflammatory effects in type 1 diab etic rats (2009)
  • Author(s): Kodera R, Kataoka H, Shikata K, Makino H
  • Organizer: Asia Islet Biology and Incretin Symposium(AIBIS)
• [Book] 慢性合併症の臨床2(腎症) 1.腎症の成因.糖尿病学の進歩 (2010)
  • Author(s): 四方賢一、槇野博史
  • Publisher: 日本糖尿病学会
• [Book] 腎不全期糖尿病最新の治療 (2010)
  • Author(s): 四方賢一
  • Publisher: 南江堂
• [Book] 糖尿病学の進歩2010 (2010)
  • Author(s): 四方賢一、槇野博史
  • Total Pages: 345
  • Publisher: 診断と治療
• [Book] 糖尿病最新の治療 (2010)
  • Author(s): 四方賢一
  • Total Pages: 310
  • Publisher: 南江堂