New therapeutic strategy for diabetic kidney disease by inhibiting MGAT
Project/Area Number |
20K21773
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 59:Sports sciences, physical education, health sciences, and related fields
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Research Institution | Kanazawa Medical University |
Principal Investigator |
古家 大祐 金沢医科大学, 医学部, 客員教授 (70242980)
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Co-Investigator(Kenkyū-buntansha) |
北田 宗弘 和歌山県立医科大学, 医学部, 博士研究員 (40434469)
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Project Period (FY) |
2020-07-30 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
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Keywords | 糖尿病 / PKC / MGAT2 / シングルセル解析 / MAPK / HK細胞 / 糖尿病性腎臓病 / SGLT-2阻害薬 / MGAT / DAG |
Outline of Research at the Start |
顕著な腎線維化を有する2型糖尿病モデル動物CD-1db/dbの腎遺伝子発現アレイ解析にて、異常解糖系遺伝子の変動が明らかとなり、我々はCD1db/dbにおいてBKSdb/dbやCD1db/mに比し有意に増加している遺伝子群の中で、monoacylglycerol Acyltransferase 2 (MGAT2)に注目した。CD1db/db腎にてDAG蓄積によりPKC・MAPK活性が増強されることも確認した。今回、「MGAT2阻害によりPKC活性化の根本であるDAG集積の抑制できればDKDの根本的治療になる」という仮説のもと解析を行うとともに発現責任細部を同定する。
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Outline of Annual Research Achievements |
db遺伝子を戻し交配にてCD-1に導入し顕著な腎線維化を有する2型糖尿病モデル動物CD-1db/dbの作成に成功した。さらに腎遺伝子発現アレイ解析にて、異常解糖系遺伝子の変動が明らかとなり、我々はCD1db/dbにおいてBKSdb/dbやCD1db/mに比し有意に増加している遺伝子群の中で、monoacylglycerol Acyltransferase 2 (MGAT2)に注目した。CD1 db/dbマウスの腎臓において、PKC-MAPKに活性化とともに、それら活性化がMGAT2阻害薬ととおに、SGLT2阻害薬治療によって改善することが見出された。single cell suspension作成と腎構成細胞の分離同定によって、PKC-MAPK活性化は糸球体構成細胞(上皮細胞、内皮細胞、メサンギウム細胞)および近位尿細管細胞に生じていることが見出された。糸球体構成細胞(上皮細胞、内皮細胞、メサンギウム細胞)の活性増加はMGAT2阻害薬によって、近位尿細管細胞の活性化はMGAT2阻害薬とSGLT2阻害薬によって相乗的に抑制された。
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Report
(3 results)
Research Products
(49 results)
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[Journal Article] Rationale, design and baseline characteristics of the effect of canagliflozin in patients with type 2 diabetes and microalbuminuria in the Japanese population: The CANPIONE study2022
Author(s)
Miyamoto S, Heerspink HJL, de Zeeuw D, Toyoda M, Suzuki D, Hatanaka T, Nakamura T, Kamei S, Murao S, Hida K, Ando S, Akai H, Takahashi Y, Koya D, Kitada M, Sugano H, Nunoue T, Nakamura A, Sasaki M, Nakatou T, Fujimoto K, Kawanami D, Wada T, Miyatake N, Yoshida M, Shikata K; CANPIONE study Investigators.
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Journal Title
Diabetes Obes Metab
Volume: 24
Issue: 8
Pages: 1429-1438
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Novel PKD2 Missense Mutation p.Ile424Ser in an Individual with Multiple Hepatic Cysts: A Case Report2022
Author(s)
Miura S, Niida Y, Hashizume C, Fujii A, Takagaki Y, Kusama K, Akazawa S, Minami T, Mukai T, Furuichi K, Tsuchishima M, Ueda N, Takamura H, Koya D, Ito T.
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Journal Title
Medicines (Basel)
Volume: 9
Issue: 4
Pages: 25-25
DOI
Related Report
Peer Reviewed
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[Journal Article] Randomized trial of an intensified, multifactorial intervention in patients with advanced-stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan)2021
Author(s)
Shikata K, Haneda M, Ninomiya T, Koya D, Suzuki Y, Suzuki D, Ishida H, Akai H, Tomino Y, Uzu T, Nishimura M, Maeda S, Ogawa D, Miyamoto S, Makino H; Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT-Japan) collaborative group.
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Journal Title
J Diabetes Investig.
Volume: 12
Issue: 2
Pages: 207-216
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] Sodium-glucose cotransporter 2 inhibitors in type 2 diabetes patients with renal function impairment slow the annual renal function decline, in a real clinical practice2021
Author(s)
Hirai T, Kitada M, Monno I, Oda E, Hayashi Y, Shimada K, Takagaki Y, Ogura Y, Fujii M, Konishi K, Sakurai M, Nakagawa A, Koya D.
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Journal Title
J Diabetes Investig.
Volume: 12
Issue: 9
Pages: 1577-1585
DOI
Related Report
Peer Reviewed
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[Journal Article] Clinical and histological features in pediatric and adolescent/young adult patients with renal disease: a cross-sectional analysis of the Japan Renal Biopsy Registry (J-RBR)2021
Author(s)
Urushihara M, Sato H, Shimizu A, Sugiyama H, Yokoyama H, Hataya H, Matsuoka K, Okamoto T, Ogino D, Miura K, Hamada R, Hibino S, Shima Y, Yamamura T, Kitamoto K, Ishihara M, Konomoto T, Hattori M; the Committee for Renal Biopsy and Disease Registry of the Japanese Society of Nephrology.
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Journal Title
Clin Exp Nephrol.
Volume: 25
Issue: 9
Pages: 1018-1026
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.2021
Author(s)
Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, Joseph A, Kolkhof P, Nowack C, Schloemer P, Ruilope LM; FIGARO-DKD Investigators.
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Journal Title
N Engl J Med.
Volume: 385
Issue: 24
Pages: 2252-2263
DOI
Related Report
Peer Reviewed
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[Journal Article] Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.2020
Author(s)
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators.
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Journal Title
N Engl J Med.
Volume: 3893
Issue: 23
Pages: 2219-2229
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Stromal cell-derived factor 1 (SDF1) attenuates platelet-derived growth factor-B (PDGF-B)-induced vascular remodeling for adipose tissue expansion in obesity2020
Author(s)
Watanabe E, Wada T, Okekawa A, Kitamura F, Komatsu G, Onogi Y, Yamamoto S, Sasahara M, Kitada M, Koya D, Tsuneki H, Sasaoka T.
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Journal Title
Angiogenesis .
Volume: 23
Issue: 4
Pages: 667-684
DOI
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Peer Reviewed / Open Access
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[Journal Article] Case report of superior mesenteric artery syndrome that developed in a lean type 2 diabetes patient and was associated with rapid body weight loss after sodium-glucose cotransporter 2 inhibitor administration2020
Author(s)
Hirai T, Kitada M, Hayashi Y, Monno I, Takagaki Y, Shimada K, Ogura Y, Fujii M, Konishi K, Nakagawa A, Koya D.
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Journal Title
J Diabetes Investig .
Volume: 11
Issue: 5
Pages: 1359-1362
DOI
Related Report
Peer Reviewed / Open Access
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