New therapeutic strategy for diabetic kidney disease by inhibiting MGAT

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K21773
• 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)
• 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)
• Project Period (FY): 2020-07-30 – 2023-03-31
• Keywords: 糖尿病 / PKC / MGAT2 / シングルセル解析 / MAPK

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。

Research Products

• [Journal Article] Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis (2023)
  • Author(s): Adhikari J, Hirai T, Kawakita E, Iwai K, Koya D, Kanasaki K.
  • Journal Title: J Diabetes Invetstig Volume: Online ahead of print. Pages: -
  • DOI: 10.1111/jdi.14017.
  • Peer Reviewed
• [Journal Article] Finerenone in Patients With Chronic Kidney Disease and Type 2 Diabetes According to Baseline HbA1c and Insulin Use: An Analysis From the FIDELIO-DKD Study (2022)
  • Author(s): Rossing P, FIDELIO-DKD Investigators.
  • Journal Title: Diabetes Care Volume: 45 Pages: 888-897
  • DOI: 10.2337/dc21-1944.
  • Peer Reviewed / Int'l Joint Research
• [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 study (2022)
  • 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.
  • Journal Title: Diabetes Obes Metab Volume: 24 Pages: 1429-1438.
  • DOI: 10.1111/dom.14731.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity (2022)
  • Author(s): Tsuneki H, Maeda T, Takata S, Sugiyama M, Otsuka K, Ishizuka H, Onogi Y, Tokai E, Koshida C, Kon K, Takasaki I, Hamashima T, Sasahara M, Rudich A, Koya D, Sakurai T, Yanagisawa M, Yamanaka A, Wada T, Sasaoka T.
  • Journal Title: Cell Rep Volume: 41 Pages: 111497
  • DOI: 10.1016/j.celrep.2022.111497.
  • Peer Reviewed
• [Journal Article] Adenosine/adenosine type 1 receptor signaling pathway did not play dominant roles on the influence of sodium-glucose cotransporter 2 inhibitor in the kidney of bovine serum albumin-overloaded streptozotocin-induced diabetic mice (2022)
  • Author(s): Shimada K, Kanasaki K, Kato M, Ogura Y, Takagaki Y, Monno I, Hirai T, Kitada M, Koya D.
  • Journal Title: J Diabetes Investig Volume: 13 Pages: 955-964
  • DOI: 10.1111/jdi.13760.
  • Peer Reviewed / Open Access
• [Journal Article] Dietary intake and physical activity in Japanese patients with type 2 diabetes: the Japan Diabetes Complication and its Prevention prospective study (JDCP study 8) (2022)
  • Author(s): Horikawa C, Tsuda K, Oshida Y, Satoh J, Hayashino Y, Tajima N, Nishimura R, Sone H; JDCP Study Group.
  • Journal Title: Dibetol Int Volume: 13 Pages: 344-357
  • DOI: 10.1007/s13340-022-00575-0.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel PKD2 Missense Mutation p.Ile424Ser in an Individual with Multiple Hepatic Cysts: A Case Report (2022)
  • 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.
  • Journal Title: Medicines (Basel) Volume: 9 Pages: 25
  • DOI: 10.3390/medicines9040025.
  • Peer Reviewed