Significance of glycan abnormalities in diabetic nephropathy

• Project/Area Number: 19H03675
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Okayama University
• Principal Investigator: Wada Jun 岡山大学, 医歯薬学域, 教授 (30294408)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,030,000 (Direct Cost: ¥13,100,000、Indirect Cost: ¥3,930,000); Fiscal Year 2021: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2019: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 糖尿病性腎症 / 尿レクチンアレイ / 網羅的糖鎖プロファイル / Ｃ型レクチン受容体 / 糖鎖合成酵素 / 糖鎖異常 / O型糖鎖 / レクチンアレイ / 糖鎖プロファイル

Outline of Research at the Start

２型糖尿病患者のコホート研究で、尿レクチンアレイ解析による糖鎖の網羅的解析を施行したところ、尿中レクチン(SNA, ABA, Jacalin, ACA, RCA120)への結合シグナルの上昇が腎機能低下のリスクであることを見出した。これらのレクチンが認識する糖鎖は糖タンパク質上のT-antigenやsialyl-Tnで、いずれも合成不全糖鎖で癌組織において発現する抗原でもある。尿中糖鎖の糖尿病性腎症のバイオマーカーとして重要性と腎症進展のメカニズムに関与を示し、糖尿病性腎症の新規治療ターゲットとしての意義を明らかにする。

Outline of Final Research Achievements

Urinary lectin array analysis was successfully developed by using 45 lectins with different glycan binding specificity. In the cohort of patients with type 2 diabetes (n=680), higher glycan binding signals to SNA, ABA, Jacalin, ACA, and RCA120 predicted the 30% eGFR decline after 4 years follow-up. The lectin histochemistry demonstrated that T-antigen, Tn-antigen, sialyl-T, sialyl-Tn, and Core 3 recognized by these lectins were localized proximal tubular cells and secreted to the urine.

Academic Significance and Societal Importance of the Research Achievements

糖尿病性腎症において近位尿細管細胞に発現するTn-antigenやsialyl-Tnと、マクロファージ上に存在しそれらの糖鎖構造を認識するC型レクチン受容体の相互作用が進展に関与している可能性を示した。今後の糖尿病性腎症の診断や治療の開発への研究の展開が期待される。

Research Products

• [Journal Article] Development of Urinary Diagnostic Biomarker for IgA Nephropathy by Lectin Microarray. (2022)
  • Author(s): Onishi Y, Mise K, Kawakita C, Uchida HA, Sugiyama H, Sugawara R, Yamaguchi S, Yoshida M, Mitsuhashi T, Yamada M, Hirabayashi J, Wada J.
  • Journal Title: Am J Nephrol. Volume: 53 Issue: 1 Pages: 10-20
  • DOI: 10.1159/000520998
  • NAID: 120007190701
  • Peer Reviewed
• [Journal Article] Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4. (2022)
  • Author(s): Yamaguchi S, Zhang D, Katayama A, Kurooka N, Sugawara R, Albuayjan HHH, Nakatsuka A, Eguchi J, Wada J.
  • Journal Title: Front Endocrinol (Lausanne). Volume: 12 Pages: 750261-750261
  • DOI: 10.3389/fendo.2021.750261
  • NAID: 120007188342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Circulating GPIHBP1 levels and microvascular complications in patients with type 2 diabetes: A cross-sectional study. (2022)
  • Author(s): Kurooka N, Eguchi J, Murakami K, Kamei S, Kikutsuji T, Sasaki S, Seki A, Yamaguchi S, Nojima I, Watanabe M, Higuchi C, Katayama A, Uchida HA, Nakatsuka A, Shikata K, Wada J.
  • Journal Title: J Clin Lipidol. Volume: 22 Issue: 2 Pages: 21-26
  • DOI: 10.1016/j.jacl.2022.01.006
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel Urinary Glycan Biomarkers Predict Cardiovascular Events in Patients With Type 2 Diabetes: A Multicenter Prospective Study With 5-Year Follow Up (U-CARE Study 2). (2021)
  • Author(s): Mise K, Imamura M, Yamaguchi S, Watanabe M, Higuchi C, Katayama A, Miyamoto S, Uchida HA, Nakatsuka A, Eguchi J, Hida K, Nakato T, Tone A, Teshigawara S, Matsuoka T, Kamei S, Murakami K, Shimizu I, Miyashita K, Ando S, Nunoue T, Yoshida M, Yamada M, Shikata K, Wada J.
  • Journal Title: Front Cardiovasc Med. Volume: 8 Pages: 668059-668059
  • DOI: 10.3389/fcvm.2021.668059
  • NAID: 120007053373
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of Mir342 in Diet-Induced Obesity Mouse and the Hypothalamic Appetite Control. (2021)
  • Author(s): Zhang D, Yamaguchi S, Zhang X, Yang B, Kurooka N, Sugawara R, Albuayjan HHH, Nakatsuka A, Eguchi J, Hiyama TY, Kamiya A, Wada J.
  • Journal Title: Front Endocrinol (Lausanne). Volume: 12 Pages: 727915-727915
  • DOI: 10.3389/fendo.2021.727915
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real- world Clinical Practice: The Japan Chronic Kidney Disease Database. (2021)
  • Author(s): Nagasu H, Yano Y, Kanegae H, Heerspink HJL, Tamura K, et al.
  • Journal Title: Diabetes Care. Volume: 44 Issue: 11 Pages: 2542-2551
  • DOI: 10.2337/dc21-1081
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of Mir223 Exacerbates Lupus Nephritis by Targeting S1pr1 in Faslpr/lpr Mice (2021)
  • Author(s): Hiramatsu-Asano Sumie、Sunahori-Watanabe Katsue、Zeggar Sonia、Katsuyama Eri、Mukai Tomoyuki、Morita Yoshitaka、Wada Jun
  • Journal Title: Frontiers in Immunology Volume: 11 Pages: 616141-616141
  • DOI: 10.3389/fimmu.2020.616141
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel urinary glycan profiling by lectin array serves as the biomarkers for predicting renal prognosis in patients with IgA nephropathy (2021)
  • Author(s): Kawakita Chieko、Mise Koki、Onishi Yasuhiro、Sugiyama Hitoshi、Yoshida Michihiro、Yamada Masao、Wada Jun
  • Journal Title: Scientific Reports Volume: 11(1) Issue: 1 Pages: 3394-3394
  • DOI: 10.1038/s41598-020-77736-1
  • NAID: 120007144312
  • Peer Reviewed / Open Access
• [Journal Article] Lgals9 deficiency ameliorates obesity by modulating redox state of PRDX2. (2021)
  • Author(s): Nunoue T, Yamaguchi S, Teshigawara S, Katayama A, Nakatsuka A, Eguchi J, Niki T, Wada J.
  • Journal Title: Sci Rep. Volume: 16 Issue: 1 Pages: 5991-5991
  • DOI: 10.1038/s41598-021-85080-1
  • NAID: 120007004155
  • Peer Reviewed / Open Access
• [Journal Article] A Vaspin-HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease (2021)
  • Author(s): Nakatsuka A, Yamaguchi S, Eguchi J, Kakuta S, Iwakura Y, Sugiyama H, Wada J.
  • Journal Title: Commun Biol . Volume: 4 Issue: 1 Pages: 373-373
  • DOI: 10.1038/s42003-021-01902-y
  • NAID: 120007004153
  • Peer Reviewed / Open Access
• [Journal Article] Adult kidney stem/progenitor cells contribute to regeneration through the secretion of trophic factors (2020)
  • Author(s): Tsuji Kenji、Kitamura Shinji、Sang Yizhen、Fukushima Kazuhiko、Wada Jun
  • Journal Title: Stem Cell Research Volume: 46 Pages: 101865-101865
  • DOI: 10.1016/j.scr.2020.101865
  • NAID: 120006887353
  • Peer Reviewed / Open Access
• [Journal Article] Association of explanatory histological findings and urinary protein and serum creatinine levels at renal biopsy in lupus nephritis: a cross-sectional study (2020)
  • Author(s): Katsuyama Eri、Miyawaki Yoshia、Sada Ken-ei、Asano Yosuke、Hayashi Keigo、Yamamura Yuriko、Hiramatsu-Asano Sumie、Morishita Michiko、Ohashi Keiji、Watanabe Haruki、Katsuyama Takayuki、Narazaki Mariko、Matsumoto Yoshinori、Wada Jun
  • Journal Title: BMC Nephrology Volume: 21(1) Issue: 1 Pages: 208-208
  • DOI: 10.1186/s12882-020-01868-9
  • NAID: 120006862797
  • Peer Reviewed / Open Access
• [Journal Article] Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice (2020)
  • Author(s): Fukushima Kazuhiko、Kitamura Shinji、Tsuji Kenji、Sang Yizhen、Wada Jun
  • Journal Title: International Journal of Molecular Sciences Volume: 21(11) Issue: 11 Pages: 4054-4054
  • DOI: 10.3390/ijms21114054
  • NAID: 120006869600
  • Peer Reviewed / Open Access
• [Journal Article] Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury (2020)
  • Author(s): Sang Yizhen、Tsuji Kenji、Inoue-Torii Akiko、Fukushima Kazuhiko、Kitamura Shinji、Wada Jun
  • Journal Title: International Journal of Molecular Sciences Volume: 21(11) Issue: 11 Pages: 4099-4099
  • DOI: 10.3390/ijms21114099
  • NAID: 120006869601
  • Peer Reviewed / Open Access
• [Journal Article] The Protective Effect of Chlorogenic Acid on Vascular Senescence via the Nrf2/HO-1 Pathway (2020)
  • Author(s): Hada Yoshiko、Uchida Haruhito A.、Otaka Nozomu、Onishi Yasuhiro、Okamoto Shugo、Nishiwaki Mariko、Takemoto Rika、Takeuchi Hidemi、Wada Jun
  • Journal Title: International Journal of Molecular Sciences Volume: 21(12) Issue: 12 Pages: 4527-4527
  • DOI: 10.3390/ijms21124527
  • NAID: 120006877909
  • Peer Reviewed / Open Access
• [Journal Article] Genetic Deletion of Vasohibin-2 Exacerbates Ischemia-Reperfusion-Induced Acute Kidney Injury (2020)
  • Author(s): Miyake Hiromasa、Tanabe Katsuyuki、Tanimura Satoshi、Nakashima Yuri、Morioka Tomoyo、Masuda Kana、Sugiyama Hitoshi、Sato Yasufumi、Wada Jun
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 12 Pages: 4545-4545
  • DOI: 10.3390/ijms21124545
  • NAID: 120006872424
  • Peer Reviewed / Open Access
• [Journal Article] Deep Learning Could Diagnose Diabetic Nephropathy with Renal Pathological Immunofluorescent Images (2020)
  • Author(s): Kitamura Shinji、Takahashi Kensaku、Sang Yizhen、Fukushima Kazuhiko、Tsuji Kenji、Wada Jun
  • Journal Title: Diagnostics Volume: 10(7) Issue: 7 Pages: 466-466
  • DOI: 10.3390/diagnostics10070466
  • NAID: 120006880205
  • Peer Reviewed / Open Access
• [Journal Article] Dysfunction of CD8 + PD-1 + T cells in type 2 diabetes caused by the impairment of metabolism-immune axis (2020)
  • Author(s): Nojima I, Eikawa S, Tomonobu N, Hada Y, Kajitani N, Teshigawara S, Miyamoto S, Tone A, Uchida HA, Nakatsuka A, Eguchi J, Shikata K, Udono H, Wada J.
  • Journal Title: Sci Rep. Volume: 10 Issue: 1 Pages: 14928-14928
  • DOI: 10.1038/s41598-020-71946-3
  • NAID: 120006891215
  • Peer Reviewed / Open Access
• [Journal Article] Dynamin 1 is important for microtubule organisation and stabilisation in glomerular podocytes (2020)
  • Author(s): The Mon La , Tachibana, H., Li, S.A., Abe, T., Seiriki, S., Nagaoka, H., Takashima, E., Takeda, T., Ogawa, D., Makino, S., Asanuma, K., Watanabe, M., Tian, X., Ishibe, S., Sakane, A., Sasaki, T., Wada, J., Takei, K., Yamada, H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 12 Pages: 16449-16463
  • DOI: 10.1096/fj.202001240rr
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of Interleukin-6 Signaling Attenuates Aortitis, Left Ventricular Hypertrophy and Arthritis in Interleukin-1 Receptor Antagonist Deficient Mice. (2020)
  • Author(s): Yoshiko Hada, Haruhito A. Uchida, Tomoyuki Mukai, Fumiaki Kojima, Masashi Yoshida, Hidemi Takeuchi, Yuki Kakio, Nozomu Otaka,Yoshitaka Morita, Jun Wada.
  • Journal Title: Clin. Sci. (Lond). Volume: 134 Issue: 20 Pages: 2771-2787
  • DOI: 10.1042/cs20201036
  • NAID: 120007168219
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Risk of higher dose methotrexate for renal impairment in patients with rheumatoid arthritis (2020)
  • Author(s): Hayashi Keigo、Sada Ken-Ei、Asano Yosuke、Asano Sumie Hiramatsu、Yamamura Yuriko、Ohashi Keiji、Morishita Michiko、Watanabe Haruki、Narazaki Mariko、Matsumoto Yoshinori、Wada Jun
  • Journal Title: Scientific Reports Volume: 10(1) Issue: 1 Pages: 18715-18715
  • DOI: 10.1038/s41598-020-75655-9
  • NAID: 120006939591
  • Peer Reviewed / Open Access
• [Journal Article] Vasohibin-2 Aggravates Development of Ascending Aortic Aneurysms But Not Abdominal Aortic Aneurysms Nor Atherosclerosis in ApoE Deficient Mice (2020)
  • Author(s): Otaka Nozomu、Uchida Haruhito A、Okuyama Michihiro、Hada Yoshiko、Onishi Yasuhiro、Kakio Yuki、Takeuchi Hidemi、Umebayashi Ryoko、Tanabe Katsuyuki、Subramanian Venkateswaran、Daugherty Alan、Sato Yasufumi、Wada Jun
  • Journal Title: American Journal of Hypertension Volume: in press Issue: 5 Pages: 467-475
  • DOI: 10.1093/ajh/hpaa181
  • Peer Reviewed
• [Journal Article] Podocyte autophagy is associated with foot process effacement and proteinuria in patients with minimal change nephrotic syndrome. (2020)
  • Author(s): Ogawa-Akiyama A, Sugiyama H, Kitagawa M, Tanaka K, Kano Y, Mise K, Otaka N, Tanabe K, Morinaga H, Kinomura M, Uchida HA, Wada J.
  • Journal Title: PLoS One. Volume: 15(1) Issue: 1 Pages: 1-15
  • DOI: 10.1371/journal.pone.0228337
  • NAID: 120006862788
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibitory Effects of Tofogliflozin on Cardiac Hypertrophy in Dahl Salt-Sensitive and Salt-Resistant Rats Fed a High-Fat Diet (2019)
  • Author(s): Kimura T, Nakamura K, Miyoshi T, Yoshida M, Akazawa K, Saito Y, Akagi S, Ohno Y, Kondo M, Miura D, Wada J, Ito H.
  • Journal Title: International Heart Journal Volume: 60 Issue: 3 Pages: 728-735
  • DOI: 10.1536/ihj.18-392
  • NAID: 130007655762
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2019-05-30
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Gut microbiome-derived phenyl sulfate contributes to albuminuria in diabetic kidney disease (2019)
  • Author(s): Kikuchi Koichi、Saigusa Daisuke、Kanemitsu Yoshitomi、Matsumoto Yotaro、Tsukamoto Hiroki、Abe Takaaki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1835-1835
  • DOI: 10.1038/s41467-019-09735-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Renal tubular injury exacerbated by Vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model. (2019)
  • Author(s): Tanimura S, Tanabe K, Miyake H, Masuda K, Tsushida K, Morioka T, Sugiyama H, Sato Y, Wada J.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 317(2)
  • Peer Reviewed / Int'l Joint Research
• [Presentation] We’re good! We fang it! Debate about SGLT2 inhibitors in DKD. Con (less aggressive/less universal use). (2019)
  • Author(s): Wada J
  • Organizer: WCN 2019
  • Int'l Joint Research / Invited
• [Presentation] 挑戦する生活習慣病の生化学－次世代の治療戦略を目指して－生活習慣病における糖鎖とレクチン (2019)
  • Author(s): 和田淳
  • Organizer: 第92回日本生化学学会大会
  • Invited