Novel therapeutic targets for diabetic nephropathy.

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 17590828
• 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 (00243452)
• Co-Investigator(Kenkyū-buntansha): MAKINO Hirofumi Okayama University, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Department of Medicine and Clinical Science, Professor (50165685) ; WADA Jun Okayama University, Hospital, Lecturer (30294408)
• Project Period (FY): 2005 – 2006
• Keywords: Diabetic nephropathy / Inflammation / Macrophage / Adhesion molecule / DNA chip / ICAM-1 / Knockout, mouse / Glomerulosclerosis

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. To find a novel therapeutic target for diabetic nephropathy, 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 tissue 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. Several genes including osteopontin, cholecystokinin (CCK) and scavenger receptor A are up-regulated in the kidneys of diabetic or 5/6 nephretomized ICAM-1(+/+) mice, while the expression levels of these genes were decreased in diabetic or 5/6 nephrectomized ICAM-1(-/-) mice as compared to ICAM-1(+/+) mice. Scavenger receptor A deficient mice revealed diminished albuminuria and renal injuries after induction of dianetes as compared with wild type mice. Renal injuries were ameliorated in CCK-receptor deficient mice after 5/6 nephrectomy as compared with wild type mice. Our results indicate that microinflammation is involved in the pathogenesis of diabetic nephropathy. CCK, scavenger receptor A and osteopontin may be novel therapeutic target for diabetic nephropathy.

Research Products

• [Journal Article] Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients. (2007)
  • Author(s): Yoshikawa R, Wada J, Seiki K, Matsuoka T, Miyamoto S, Takahashi K, Ota S, Taniai K, Hida K, Yamakado M, Shikata K, Uehara Y, Urade Y, Makino H.
  • Journal Title: Diabetes Res Clin Pract. 76・3 Pages: 358-367
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation. (2007)
  • Author(s): Ohga S, Shikata K, Yozai K, Okada S, Ogawa D, Usui H, Wada J, Shikata Y, Makino H.
  • Journal Title: Am J Physiol Renal Physiol. 292・4 Pages: F1141-1150
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation. (2007)
  • Author(s): Usui HK, Shikata K, Sasaki M, Okada S, Matsuda M, Shikata Y, Ogawa D, Kido Y, Nagase R, Yozai K, Ohga S, Tone A, Wada J, Takeya M, Horiuchi S, Kodama T, Makino H.
  • Journal Title: Diabetes 56・2 Pages: 363-372
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis. (2007)
  • Author(s): Tabuchi M, Inoue K, Usui-Kataoka H, Kobayashi K, Teramoto M, Takasugi K, Shikata K, Yamamura M, Ando K, Nishida K, Kasahara J, Kume N, Lopez LR, Mitsudo K, Nobuyoshi M, Yasuda T, Kita T, Makino H, Matsuura E.
  • Journal Title: J Lipid Res. 48・4 Pages: 768-781
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Changes of gene expression profiles in macrophages stimulated by angiotensin II-angiotensin II induces MCP-2 through AT1-receptor. (2007)
  • Author(s): Tone A, Shikata K, Ogawa D, Sasaki S, Nagase R, Sasaki M, Yozai K, Usui HK, Okada S, Wada J, Shikata Y, Makino H.
  • Journal Title: J Renin Angiotensin Aldosterone Syst. 8・1 Pages: 45-50
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells. Am J Physiol Cell Physiol. 2007 Nov;293(5):C1523-31.Epub2007Aug8. (2007)
  • Author(s): Omori K, Shikata Y, Sarai K, Watanabe N, Wada J, Goda N, Kataoka N, Shikata K, Makino H.
  • Journal Title: Am J Physiol Cell Physiol. 263・5 Pages: 1523-1531
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Urinary PGDS levels are associated with vascular injury in type 2 diabetes patients (2007)
  • Author(s): Yoshikawa, R., Wada, J., Seiki, K., Matsuoka, T., Miyamoto, S., Takahashi, K., Ota, S., Taniai, K., Hida, K., Yamakado, M., Shikata, K., Uehara, Y., Urade, Y., Makino, H
  • Journal Title: Diabetes Res Clin Pract 76(3) Pages: 358-367
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation (2007)
  • Author(s): Ohga, S., Shikata, K., Yozai, K., Okada, S., Ogawa, D., Usui, H., Wada, J., Shikata, Y., Makino, H
  • Journal Title: Am J Physiol Renal Physiol 292(4) Pages: 1141-1150
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Macrophage scavenger receptor-a-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation (2007)
  • Author(s): Usui, HK., Shikata, K., Sasaki, M., Okada, S., Matsuda, M., Shikata, Y., Ogawa, D., Kido, Y., Nagase, R., Yozai, K., Ohga, S., Tone, A., Wada, J., Takeya, M., Horiuchi, S., Kodama, T., Makino, H
  • Journal Title: Diabetes 56(2) Pages: 363-372
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The association of C-reactive protein with an oxidative metabolite of LDL and its implication in atherosclerosis (2007)
  • Author(s): Tabuchi, M., Inoue, K., Usui-Kataoka, H., Kobayashi, K., Teramoto, M., Takasugi, K., Shikata, K., Yamamura, M., Ando, K., Nishida, K., Kasahara, J., Kume, N., Lopez, LR., Mitsudo, K., Nobuyoshi, M., Yasuda, T., Kita, T., Makino, H., Matsuura, E
  • Journal Title: J Lipid Res 48(4) Pages: 768-781
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Changes of gene expression profiles in macrophages stimulated by angiotensin II-angiotensin II induces MCP-2 through AT1-receptor (2007)
  • Author(s): Tone, A., Shikata, K., Ogawa, D., Sasaki, S., Nagase, R., Sasaki, M., Yozai, K., Usui, HK., Okada, S., Wada, J., Shikata, Y., Makino, H
  • Journal Title: J Renin Angiotensin Aldosterone 8(1) Pages: 45-50
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Edaravone mimics sphingosine-1-phosphate-induced endothelial barrier enhancement in human microvascular endothelial cells (2007)
  • Author(s): Omori, K., Shikata, Y., Sarai, K., Watanabe, N., Wada, J., Goda, N., Kataoka, N., Shikata, K., Makino, H
  • Journal Title: Am J Physiol Cell Physiol 293(5) Pages: 1523-1531
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Therapeutic approach for diabetic nephropathyusing gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production. (2006)
  • Author(s): Zhang Y, Wada J, Hashimoto I, Eguchi J, Yasuhara A, Kanwar YS, Shikata K, Makino H.
  • Journal Title: J Am Soc Nephrol. Apr. 17・4 Pages: 1090-1101
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms (2006)
  • Author(s): Okada T, Wada J, Hida K, Eguchi J, Hashimoto I, Baba M, Yasuhara A, Shikata K, Makino H.
  • Journal Title: Diabetes.2006 Jun;55(6):1666-77 55・6 Pages: 1666-1677
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Elevated serum monocyte chemoattractant protein-4 and chronic inflammation in overweight subjects. (2006)
  • Author(s): Hashimoto I, Wada J, Hida A, Baba M, Miyatake N, Eguchi J, Shikata K, Makino H.
  • Journal Title: Obesity (Silver Spring) 14・5 Pages: 799-811
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Therapeutic approach for diabetic nephropathy using gene delivery of translocase of inner mitochondrial membrane 44 by reducing mitochondrial superoxide production (2006)
  • Author(s): Zhang, Y., Wada, J., Hashimoto, I., Eguchi, J., Yasuhara, A., Kanwar, YS., Shikata, K., Makino, H
  • Journal Title: Am Soc Nephrol 17(4) Pages: 1090-1010
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Thiazolidinediones ameliorate diabetic nephropathy via cell cycle-dependent mechanisms (2006)
  • Author(s): Okada, T., Wada, J., Hida, K., Eguchi, J., Hashimoto, I., Baba, M., Yasuhara, A., Shikata, K., Makino, H
  • Journal Title: Diabetes 55(6) Pages: 1666-1677
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Elevated serum monocyte chemoattractant protein-4 and chronic inflammation in overweight subjects (2006)
  • Author(s): Hashimoto, I., Wada, J., Hida, A., Baba, M., Miyatake, N., Eguchi, J., Shikata, K., Makino, H
  • Journal Title: Obesity (Silver Spring) 14(5) Pages: 799-811
  • Description: 「研究成果報告書概要(欧文)」より