Role of Macrophage in the pathogenesis of diabetic nephropathy and novel therapeutic target.

• Project/Area Number: 15590850
• 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 Okayama University, Hospital, Lecturer, 医学部歯学部附属病院, 講師 (00243452)
• Co-Investigator(Kenkyū-buntansha): MAKINO Hirofumi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Department of Medicine and Clinical Science, Professor, 大学院・医歯薬学総合研究科, 教授 (50165685) ; 和田 淳 岡山大学, 医学部歯学部附属病院, 講師 (30294408)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2003: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: Diabetic nephropathy / Macrophage / Kidney / Inflammation / ICAM-1 / Glomerulus / Interstitium / TGF-β / DNAアレイ / ケモカイン / 糖尿病 / ICMA-1 / マイクロファージ

Research Abstract

Diabetic nephropathy is a leading cause of end-stage renal failure. Several mechanisms, including activation of protein kinase C, advanced glycation end products, and overexpression of transforming growth factor (TGF)-beta, are believed to be involved in the pathogenesis of diabetic nephropathy. However, the significance of inflammatory processes in the pathogenesis of diabetic microvascular complications is poorly understood. Accumulation of macrophages and overexpression of leukocyte adhesion molecules and chemokines are prominent in diabetic human kidney tissues. We previously demonstrated that intercellular adhesion molecule (ICAM)- 1 mediates macrophage infiltration into the diabetic kidney. In the present study, to investigate the role of macrophage in diabetic nephropathy and find a novel therapeutic target, we induced diabetes or 5/6 nepphrectomy in ICAM-1-deficient (ICAM-1(-/-)) mice and ICAM-1(+/+) mice and examined the renal pathology over a period of 6 months. The infiltration of macrophages, albuminuria anc renal tiossue injuries were markedly suppressed in diabetic ICAM-1(-/-) mice or 5/6 nephrectomized ICAM-1(-/-) mice compared with ICAM-1(+/+) mice. We investigated the gene expression profiles in the kidneys of these mice using DNA microarray system. Proinflammatory geses including osteopontin are up-regulated in the kidneys of diabetic or 5/6 nephrectomized ICAM-1(+/+) mice, while the expression levels of these genes were decresased in diabetic or 5/6nephrectomized ICAM-1(-/-) mice as compared to ICAM-1(+/+) mice. These genes might be novel targets for the therapy of diabetic nephropathy.

Research Products

• [Journal Article] Identification of adipocyte adhesion molecule (ACAM), a novel CTX gene family, implicated in adipocyte maturation and development of obesity. (2005)
  • Author(s): Eguchi J, Wada J, Hida K, Zhang H, Matsuoka T, Baba M, Hashimoto I, Shikata K, Ogawa N, Makino H.
  • Journal Title: Biochem J. 5 Pages: 343-353
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sulfated hyaluronic acid, a potential selectin inhibitor, ameliorates experimentally induced crescentic glomerulonephritis. (2005)
  • Author(s): Ogawa D, Shikata K, Matsuda M, Akima K, Iwahashi M, Okada S, Tsuchiyama Y, Shikata Y, Wada J, Makino H.
  • Journal Title: Nephron Exp Nephrol gg:e Pages: 26-32
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Pathological roles of advanced glycation end product receptors SR-A and CD36. (2005)
  • Author(s): Horiuchi S, Unno Y, Usui H, Shikata K, Takaki K, Koito W, Sakamoto Y, Nagai R, Makino K, Sasao A, Wada J, Makino H
  • Journal Title: Ann N Y Acad Sci. 1043 Pages: 671-6752
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Visceral adipose tissue-derived serine protease inhibitor : a unique insulin-sensitizing adipocytokine in obesity. (2005)
  • Author(s): Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS.
  • Journal Title: Proc Natl Acad Sci USA 26 Pages: 10610-10615
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Clinical features of non-diabetic renal diseases in patients with type 2 diabetes. (2005)
  • Author(s): Tone A, Shikata K, Matsuda M, Usui H, Okada S, Ogawa D, Wada J, Makino H.
  • Journal Title: Diabetes Res pract. 69 Pages: 237-242
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory actions. (2005)
  • Author(s): Yozai K, Shikata K, Sasaki M, Tone A, Ohga S, Usui H, Okada S, Wada J, Nagase R, Ogawa D, Shikata Y, Makino H.
  • Journal Title: J Am Soc Nephrol. 16 Pages: 3326-3338
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. (2005)
  • Author(s): Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, Yasuhara A, Shikata K, Kanwar YS, Makino H.
  • Journal Title: J. Am Soc Nephrol. 16 Pages: 3222-3234
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats. (2005)
  • Author(s): Tone A, Shikata K, Sasaki M, Ohga S, Yozai K, Nishishita S, Usui H, Nagase R, Ogawa D, Okada S, Shikata Y, Wada J, Makino H.
  • Journal Title: Diabetologia. 48 Pages: 2402-2411
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. (2005)
  • Author(s): Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, Itoshima T, Makino H.
  • Journal Title: Diabetes Care. 28;, 2005. 28 Pages: 2890-2895
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sulfated hyaluronic acid, a potential selectin inhibitor, ameliorates experimentally induced crescentic glomerulonephritis. (2005)
  • Author(s): Ogawa D, Shikata K, Matsuda M, Akima K, Iwahashi M, Okada S, Tsuchiyama Y, Shikata Y, Wada J, Makino H.
  • Journal Title: Nephron Exp Nephrol. 99
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pathological roles of advanced glycation end product receptors SR-A and CD36. (2005)
  • Author(s): Horiuchi S, Unno Y, Ushi H, Shikata K, Takaki K, Koito W, Sakamoto Y, Nagai R, Makino K, Sasao A, Wada J, Makino H
  • Journal Title: Ann N Y Acad Sci. 1043 Pages: 671-675
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Visceral adipose tissue-derived serine protease inhibitor : a unique insulin-sensitizing adipocytokine in obesity. (2005)
  • Author(s): Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS.
  • Journal Title: Proc Natl Acad Sci USA. 26 Pages: 10610-10615
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical features of non-diabetic renal diseases in patients with type 2 diabetes. (2005)
  • Author(s): Tone A, Shikata K, Matsuda M, Usui H, Okada S, Ogawa D, Wada J, Makino H.
  • Journal Title: Diabetes Res Clin Pract. 69 Pages: 237-242
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Galectin-9 inhibits glomerular hypertrophy in db/db diabetic mice via cell-cycle-dependent mechanisms. (2005)
  • Author(s): Baba M, Wada J, Eguchi J, Hashimoto I, Okada T, Yasuhara A, Shikata K, Kanwar YS, Makino H.
  • Journal Title: J Am Soc Nephrol. 16 Pages: 3326-3338
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Erythromycin ameliorates renal injury via anti-inflammatory effects in experimental diabetic rats. (2005)
  • Author(s): Tone A, Shikata K, Sasaki M, Ohga S, Yozaki K, Nishishita S, Usui H, Nagase R, Ogawa D, Okada S, Shikata Y, Wada J, Makino H.
  • Journal Title: Diabetologia. 48 Pages: 2402-2411
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. (2005)
  • Author(s): Nakamura A, Shikata K, Hiramatsu M, Nakatou T, Kitamura T, Wada J, Itoshima T, Makino H.
  • Journal Title: Diabetes Care. 28 Pages: 2890-2895
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. (2004)
  • Author(s): Hiragushi K, Wada J, Eguchi J, Matsuoka T, Yasuhara A, Hashimoto I, Yamashita T, Hida K, Nakamura Y, Shikata K, Minamino N, Kangawa K, Makino H.
  • Journal Title: Kdney Int. 65 Pages: 540-550
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. (2004)
  • Author(s): Hiragushi K, Wada J, Eguchi J, Matsuoka T, Yasuhara A, Hashimoto I, Yamashita T, Hida K, Nakamura Y, Shikata K, Minamino N, Kangawa K, Makino H.
  • Journal Title: Kidney Int. 65 Pages: 540-550
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats. (2004)
  • Author(s): Hiragushi K et al.
  • Journal Title: Kidney International 65 Pages: 540-550
• [Journal Article] Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction. (2003)
  • Author(s): Ogawa D, Shikata K, Honke K, Sato S, Matsuda M, Nagase R, Tone A, Okada S, Usui H, Wada J, Miyasaka M, Kawashima H; Suzuki Y, Suzuki T, Taniguchi N, Hirahara Y, Tadano-Aritomi K, Ishizuka I, Tedder TF, Makino H.
  • Journal Title: J Biol Chem 279 Pages: 2085-2090
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction. (2003)
  • Author(s): Ogawa D, Shikata K, Honke K, Sato S, Matsuda M, Nagase R, Tone A, Okada S, Usui H, Wada J, Miyasaka M, Kawashima H, Suzuki Y, Suzuki T, Taniguchi N, Hirahara Y, Tadano-Aritomi K, Ishizuka I, Tedder TF, Makino H.
  • Journal Title: J Biol Chem. 279 Pages: 2085-2090
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical features of non-diabetic renal diseases in patients with type 2 diabetes
  • Author(s): Tone A et al.
  • Journal Title: Diabetes Reseach and Clinical Practice (in press)
• [Publications] Okada S, Shikata. K et al.: "Intercellular adhesion molcule-1-deficient mice are resistant against renal injury after induction of diabetes"Diabetes. 52. 2586-2593 (2003)
• [Publications] Ogawa D, Shikata K et al.: "Cerebroside sulfotransferase deficiency ameliorates L-selectin-dependent monocyte infiltration in the kidney after ureteral obstruction"J Biol Chem. 16. 2085-2090 (2004)
• [Publications] Seida A et al.: "Serum bFGF levels are reduced in Japanese overweight men and restored by a 6-month exercise education"Int J Obes Relat Metab Disord. 27. 1325-1331 (2003)
• [Publications] Hiragushi K et al.: "The role of adrenomedullin and receptors in glomerular hyperfiltration in streptozotocin-induced diabetic rats"Kidney Int. 65. 540-550 (2004)