The mechanism of brain-renal interaction on metabolic syndrome-role of AGEs-RAGE system-

• Project/Area Number: 16K09637
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kurume University
• Principal Investigator: FUKAMI KEI 久留米大学, 医学部, 教授 (80309781)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: AGEs / RAGE / AGEs-RAGE / 高血圧症 / aptamer / 糖尿病 / SGLT2 / Diabetic Nephropathy / 脳腎連関 / アプタマー / 母体環境 / メタボリック症候群 / 腎臓病

Outline of Final Research Achievements

Advanced glycation endproducts (AGEs) stimulate intracellular pathways through the receptor for AGEs (RAGE), which is thought to be involved in the brain-kidney injury. Uninephrectomized 8-week-old C57Bl/6J male mice were divided into three groups; 4% salt diet (control), 4% salt diet with DOCA (50mg), and DOCA with hydralazine (Hyd).Administration of DOCA significantly increased UAE independent of blood pressure. Renal RAGE protein expression and plasma carboxymethyl lysine (CML) levels were elevated in DOCA-induced HN mice. RAGE was co-localized with MR in podocytes by immunohistochemical analysis. DOCA-induced increase in UAE, renal ROS generation, RAGE expression, plasma CML levels, GTP-bound Rac1 activation, and MR overexpression were significantly inhibited by the administration of RAGE-aptamer. AGEs-RAGE axis and Rac1-MR pathway may be correlated with each other, which could lead to kidney injury in HN. Next we investigate the role of AGEs-RAGE system on brain-kidney injury.

Academic Significance and Societal Importance of the Research Achievements

わが国の現状の問題点として、慢性腎臓病患者の増大、とりわけ透析患者数の増大と、脳卒中罹患の増加がある。脳と腎臓はお互いに連携を取り合っている可能性が示唆されており、今回はAGEs-RAGE系に着目して研究を行った。AGEs-RAGE系の活性化に今回脳傷害にも重要な因子であるMRが関与していることが明らかとなり、AGEs-RAGE-MR系の遮断のために我々はRAGEノックアウトマウス、RAGE-aptamerを使用して検討を行った結果、RAGEを遮断することで腎傷害が著明に改善することを突き止めた。今後は創薬を念頭に脳傷害に対するRAGE-aptamerの効果を検討していく予定である。

Research Products

• [Journal Article] 特集 動脈硬化とカルシウム～カルシウムパラドックスの謎に迫る～ Seminar CKD-MBDにおけるAGEs-RAGE系の役割ｖ (2019)
  • Author(s): Fujisawa H, Nakayama Y, Ueda K, Fukami K
  • Journal Title: CLINICAL CALCIUM Volume: 29 Issue: 2 Pages: 193-198
  • DOI: 10.20837/4201902193
  • ISSN: 0917-5857
  • Year and Date: 2019-02-28
  • Peer Reviewed
• [Journal Article] Crucial role of rage in inappropriate increase of smooth muscle cells from patients with pulmonary arterial hypertension. (2018)
  • Author(s): Nakamura K, Sakaguchi M, Matsubara H, Akagi S, Sarashina T, Ejiri K, Akazawa K, Kondo M, Nakagawa K, Yoshida M, Miyoshi T, Ogo T, Oto T, Toyooka S, Higashimoto Y, Fukami K, Ito H.
  • Journal Title: PLoS One Volume: 13 Issue: 9 Pages: 1-11
  • DOI: 10.1371/journal.pone.0203046
  • Peer Reviewed / Open Access
• [Journal Article] Advanced glycation end products evoke inflammatory reactions in proximal tubular cells via autocrine production of dipeptidyl peptidase-4 (2018)
  • Author(s): Kaifu Kumiko、Ueda Seiji、Nakamura Nobutaka、Matsui Takanori、Yamada-Obara Nana、Ando Ryotaro、Kaida Yusuke、Nakata Masami、Matsukuma-Toyonaga Maki、Higashimoto Yuichiro、Fukami Kei、Suzuki Yusuke、Okuda Seiya、Yamagishi Sho-ichi
  • Journal Title: Microvascular Research Volume: 120 Pages: 90-93
  • DOI: 10.1016/j.mvr.2018.07.004
  • Peer Reviewed / Open Access
• [Journal Article] Decline in estimated glomerular filtration rate is associated with risk of end-stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS. (2018)
  • Author(s): Shimizu M, Furuichi K, Toyama T, Funamoto T, Kitajima S, Hara A, Ogawa D, Koya D, Ikeda K, Koshino Y, Kurokawa Y, Abe H, Mori K, Nakayama M, Konishi Y, Samejima K, Matsui M, Yamauchi H, Gohda T, Fukami K et al
  • Journal Title: Clin Exp Nephrol Volume: 22 Issue: 2 Pages: 377-387
  • DOI: 10.1007/s10157-017-1467-9
  • Peer Reviewed / Open Access
• [Journal Article] RAGE-aptamer Blocks the Development and Progression of Experimental Diabetic Nephropathy. (2017)
  • Author(s): Matsui, T., Higashimoto, Y., Nishino, Y., Nakamura, N., Fukami, K., Yamagishi, S.
  • Journal Title: Diabetes Volume: 66 Issue: 1 Pages: 1683-1695
  • DOI: 10.1038/s41598-018-21176-5
  • NAID: 40021434304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia. (2017)
  • Author(s): Yokoro M, Nakayama Y, Yamagishi SI, Ando R, Sugiyama M, Ito S, Yano J, Taguchi K, Kaida Y, Saigusa D, Kimoto M, Abe T, Ueda S, Fukami K
  • Journal Title: J Am Soc Nephrol Volume: 28 Issue: 9 Pages: 2670-2680
  • DOI: 10.1681/asn.2016111184
  • Peer Reviewed
• [Journal Article] RAGE-aptamer inhibits the growth and liver metastasis of melanoma in nude mice. (2017)
  • Author(s): Nakamura, N., Matsui, T., Ishibashi, Y., Sotokawauchi, A., Fukami, K., Higashimoto, Y., Yamagishi, S.
  • Journal Title: Mol. Med. Volume: 23 Issue: 1 Pages: 295-306
  • DOI: 10.2119/molmed.2017.00099
  • Peer Reviewed / Open Access
• [Journal Article] L-carnitine supplementation improves self-rating depression scale scores in uremic male patients undergoing hemodialysis (2017)
  • Author(s): Kyoko Tashiro, Yusuke Kaida, Sho-ichi Yamagishi, Hideharu Tanaka, Miyuki Yokoro, Junko Yano, Kazuko Sakai, Yuka Kurokawa, Kensei Taguchi, Yosuke Nakayama, Takahiro Inokuchi, Kei Fukami
  • Journal Title: Letters in Drug Design & Discovery Volume: 印刷中
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Compared effects of calcium and sodium polystyrene sulfonate on mineral and bone metabolism and volume overload in pre-dialysis patients with hyperkalemia (2017)
  • Author(s): Yosuke Nakayama, Kaoru Ueda, Sho-ichi Yamagishi, Miki Sugiyama, Chika Yoshida, Yuka Kurokawa, Nao Nakamura, Tomofumi Moriyama, Goh Kodama, Tomohisa Minezaki, Sakuya Ito, Akiko Nagata, Kensei Taguchi, Junko Yano, Yusuke Kaida, Kazutaka Shibatomi, Kei Fukami
  • Journal Title: Clinical and Experimental Nephrology Volume: 印刷中 Issue: 1 Pages: 35-44
  • DOI: 10.1007/s10157-017-1412-y
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] AGEs-RAGE system as a promising therapeutic target for diabetic kidney disease (2017)
  • Author(s): Kei Fukami
  • Organizer: ERA-EDTA 2017
  • Int'l Joint Research / Invited
• [Presentation] Increased sodium chloride cotransporter expression in a rat remnant kidney model (2017)
  • Author(s): Sakuya Ito, Kensei Taguchi, Yosuke Nakayama, Yusuke Kaida, Eisei Sohara, Shinichi Uchida, Kei Fukami
  • Organizer: ERA-EDTA 2017
  • Int'l Joint Research
• [Presentation] DNA-aptamer raised against RAGE improves the development of lupus nephritis in MRL/lpr mice (2017)
  • Author(s): Kensei Taguchi, Akito Maeshima, Sho-ichi Yamagishi, Yosuke Nakayama, Yusuke Kaida, Yuichiro Higashimoto, Yasuhiko Yamamoto , Craig Brooks, Kei Fukami
  • Organizer: ASN 2017
  • Int'l Joint Research
• [Presentation] 腎不全モデルラットにおけるNa-Cl共輸送体(NCC)発現の検討 (2017)
  • Author(s): 伊藤佐久耶、田口顕正、安藤亮太郎、中山陽介、甲斐田裕介、蘇原映誠、内田信一、深水圭
  • Organizer: 日本腎臓学会学術集会