Elucidation of pathophysiology and development of new therapeutic agents for preeclampsia through complement inhibition

• Project/Area Number: 21K09447
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Osaka University
• Principal Investigator: Mimura Kazuya 大阪大学, 医学部附属病院, 特任准教授(常勤) (50437422)
• Co-Investigator(Kenkyū-buntansha): 冨松 拓治 大阪大学, 大学院医学系研究科, 招へい教授 (30346209) ; 遠藤 誠之 大阪大学, 大学院医学系研究科, 教授 (30644794) ; 中村 仁美 大阪大学, 大学院医学系研究科, 助教 (80467571)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 妊娠高血圧症候群（HDP） / 血管新生因子 / Placental growth factor / 漢方薬 / Drug repositioning / Placental growth factor / placental grouth factor

Outline of Research at the Start

妊娠高血圧症候群（HDP）の薬剤治療として、PlGF（placental growth factor）を増加させる薬剤をDrug repositioningの手法を用いて探索する。本研究では、漢方薬ライブラリーを用い、in-vitro検討において胎盤・血管内皮両方からPlGF発現を促進する薬剤をスクリーニングし、その後in-vivoで検討を行う。さらに今回は効果のある漢方に共通する生薬を抽出することで、より効果の高い生薬の組み合わせを導き出す。

Outline of Final Research Achievements

In this study, we focused on the pathogenesis of Hypertensive Disorders of Pregnancy (HDP), and used a Kampo (Chinese herbal medicine) library to screen for drugs that promote PlGF (placental growth factor) expression from the placenta and vascular endothelium in an in-vitro study. We have discovered and reported a drug that promotes PlGF expression from both the placenta and vascular endothelium. We are currently evaluating the outcome of pregnancy using a mouse model of gestational hypertension. Based on the above studies, the optimal dosage, timing and duration of administration will also be considered. We are also searching for combinations of herbal medicines that are even more effective by extracting the herbal medicines that are common to effective Kampo drugs.

Academic Significance and Societal Importance of the Research Achievements

妊娠高血圧症候群の中でも妊娠高血圧腎症は胎児・母体死亡の主な原因となり全妊娠の5-8%に発症し分娩の高年化に伴い増加している。日本における妊娠高血圧症候群はHypertensive Disorders of Pregnancy（HDP）と改名され、決して軽症な病態はなく直ぐに治療に取り掛かるべき疾患だという啓発が進んでいる。未だ治療は分娩のみで薬物療法は確立していない。母体・胎児健康の為にも治療薬開発に寄与する事は現在の周産期医学において非常に重要である。日本での臨床使用経験も長い安全性の高い漢方薬からDrug repositioningの手法を用いて新たな薬剤を見いだせれば非常に意義深い。

Research Products

• [Journal Article] Severe hemolysis, elevated liver enzymes, and low platelet syndrome requiring differentiation of thrombotic microangiopathy: Four cases from a nationwide survey in Japan (2024)
  • Author(s): Komatsu Reina、Mimura Kazuya、Matsuyama Tatsuya、Kawanishi Yoko、Nakamura Hitomi、Tomimatsu Takuji、Endo Masayuki、Kimura Tadashi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: - Issue: 7 Pages: 1258-1262
  • DOI: 10.1111/jog.15949
  • Peer Reviewed / Open Access
• [Journal Article] Pregnancy outcomes in patients with IgA vasculitis with nephropathy (Henoch–Schönlein purpura nephritis) and those with IgA nephropathy: Childhood purpura nephritis is high risk for preeclampsia (2023)
  • Author(s): Mimura Kazuya、Kawanishi Yoko、Toda Aska、Miyake Tatsuya、Hiramatsu Kosuke、Kimura Toshihiro、Endo Masayuki、Kimura Tadashi
  • Journal Title: Hypertension Research in Pregnancy Volume: 11 Issue: 2 Pages: 17-24
  • DOI: 10.14390/jsshp.HRP2022-014
  • ISSN: 2187-5987, 2187-9931
  • Year and Date: 2023-05-31
  • Peer Reviewed / Open Access
• [Journal Article] A multicenter prospective study of home blood pressure measurement (HBPM) during pregnancy in Japanese women (2022)
  • Author(s): Suzuki Yoshikatsu、Matsubara Keiichi、Watanabe Kazushi、Tanaka Kanji、Yamamoto Tamao、Nohira Tomoyoshi、Mimura Kazuya、Suzuki Hirotada、Hamada Fumiaki、Makino Shintarou、Koide Keiko、Nishizawa Haruki、Naruse Katsuhiko、Mikami Yukiko、Kawabata Ikuno、Yoshimatsu Jun、Suzuki Kohta、Saito Shigeru
  • Journal Title: Hypertension Research Volume: 45 Issue: 10 Pages: 1563-1574
  • DOI: 10.1038/s41440-022-00992-3
• [Journal Article] Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan (2022)
  • Author(s): Ohkuchi Akihide、Suzuki Hirotada、Matsubara Keiichi、Watanabe Kazushi、Saitou Takuya、Oda Hideyuki、Obata Soichiro、Kondo Shinya、Noda Kiyoshi、Miyoshi Junya、Ikenoue Satoru、Nomiyama Makoto、Seki Hiroyuki、Sukegawa Sachi、Ichigo Satoshi、Ando Hirofumi、Mimura Kazuya、Saito Shigeru
  • Journal Title: Hypertension Research Volume: 45 Issue: 11 Pages: 1679-1689
  • DOI: 10.1038/s41440-022-01013-z
• [Journal Article] Prevalence of chronic hypertension and white coat hypertension in women presenting with at least one hypertension level ontwo to three consecutive measurements in a clinical setting at <20 weeks of gestation (JP-WCH1 study): A multicenter prospective cohort study (2022)
  • Author(s): Hirashima, C., Mimura, K., Ohmaru-Nakanishi, T., Kotera, K., Takahashi, K., Saito, S., Seki, H., Watanabe, K., Naruse, K., Makino, S., Metoki, H., Matsubara, S., Ichihara, A.Ohkuchi, A.
  • Journal Title: Hypertens Res Pregnancy Volume: 10 Pages: 101-107
• [Journal Article] Maternal and perinatal outcomes according to blood pressure levels for prehyp ertension: A review and meta-analysis (2022)
  • Author(s): Suzuki, H., Takagi, K., Matsubara, K., Mito, A., Kawasaki, K., Nanjo, S., Mimura, K., Bokuda, K., Makino, S., Nakamoto, O., Ichihara, A.Seki, H.
  • Journal Title: Hypertension Research in pregnancy Volume: 10 Pages: 29-39
• [Journal Article] A Review of the Best Practice Guide 2021 for the Diagnosis and Management of Hypertensive Disorders of Pregnancy (HDP) (2022)
  • Author(s): Takagi, K., Nakamoto, O., Watanabe, K., Tanaka, K., Matsubara, K., Kawabata, I., Iriyama, T., Koide, K., Kondoh, E., Suzuki, H., Takahashi, N., Makino, S., Mimura, K., Mito, A., Takeda, J., Yamasaki, M., Saito, S., Ichihara, A.Seki, H
  • Journal Title: Hypertension Research in pregnancy Volume: 10 Pages: 57-73
• [Journal Article] Atypical preeclampsia before 20 weeks of gestation with multicystic placenta, hyperreactio luteinalis, and elevated sFlt-1/PlGF ratio as manifestations of fetal triploidy: A case report (2022)
  • Author(s): Hayashida Harue、Nakamura Koji、Ukon Koto、Sato Kazuaki、Mimura Kazuya、Kakuda Mamoru、Toda Aska、Miyake Tatsuya、Hiramatsu Kosuke、Kimura Toshihiro、Endo Masayuki、Kimura Tadashi
  • Journal Title: Case Reports in Women's Health Volume: 33 Pages: e00379-e00379
  • DOI: 10.1016/j.crwh.2021.e00379
• [Journal Article] Atypical preeclampsia without underlying disease and elevated sFlt-1/PlGF ratio (2022)
  • Author(s): Mimura Kazuya、Tomimatsu Takuji、Endo Masayuki、Kimura Tadashi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 48 Issue: 2 Pages: 471-476
  • DOI: 10.1111/jog.15117
  • Peer Reviewed / Open Access
• [Journal Article] 妊娠34～36週での非重症HDP 早期誘発 (2022)
  • Author(s): 味村和哉
  • Journal Title: 東京医学社 周産期医学 Volume: 52 Pages: 1752-1755
• [Journal Article] The association of endometriosis with placenta previa and postpartum hemorrhage: a systematic review and meta-analysis (2021)
  • Author(s): Matsuzaki Shinya、Nagase Yoshikazu、Ueda Yutaka、Lee Misooja、Matsuzaki Satoko、Maeda Michihide、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Endo Masayuki、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: American Journal of Obstetrics &amp; Gynecology MFM Volume: 3 Issue: 5 Pages: 100417-100417
  • DOI: 10.1016/j.ajogmf.2021.100417
  • Peer Reviewed
• [Journal Article] Placenta previa with posterior extrauterine adhesion: clinical features and management practice (2021)
  • Author(s): Nagase Yoshikazu、Matsuzaki Shinya、Endo Masayuki、Hara Takeya、Okada Aiko、Mimura Kazuya、Hiramatsu Kosuke、Kakigano Aiko、Nakatsuka Erika、Miyake Tatsuya、Takiuchi Tsuyoshi、Ueda Yutaka、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: BMC Surgery Volume: 21 Issue: 1 Pages: 10-10
  • DOI: 10.1186/s12893-020-01027-9
  • Peer Reviewed / Open Access
• [Journal Article] A systematic review and meta-analysis of obstetric and maternal outcomes after prior uterine artery embolization (2021)
  • Author(s): Matsuzaki Shinya、Lee Misooja、Nagase Yoshikazu、Jitsumori Mariko、Matsuzaki Satoko、Maeda Michihide、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Ueda Yutaka、Tomimatsu Takuji、Endo Masayuki、Kimura Tadashi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 16914-16914
  • DOI: 10.1038/s41598-021-96273-z
  • Peer Reviewed / Open Access
• [Journal Article] Complement activation by an angiogenic imbalance leads to systemic vascular endothelial dysfunction: A new proposal for the pathophysiology of preeclampsia. (2021)
  • Author(s): Matsuyama T, Tomimatsu T, Mimura K, Yagi K, Kawanishi Y, Kakigano A, Nakamura H, Endo M, Kimura T.
  • Journal Title: J Reprod Immunol Volume: 145 Pages: 103322-103322
  • DOI: 10.1016/j.jri.2021.103322
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The RPOC long axis is a simple indicator for predicting the need of invasive strategies for secondary postpartum hemorrhage in either post-abortion or post-partum women: a retrospective case control study (2021)
  • Author(s): Kobayashi Mariya、Nakagawa Satoshi、Kawanishi Yoko、Masuda Tatsuo、Maenaka Takahide、Toda Aska、Miyake Tatsuya、Hiramatsu Kosuke、Miyoshi Ai、Mimura Kazuya、Kimura Toshihiro、Endo Masayuki、Kimura Tadashi
  • Journal Title: BMC Pregnancy and Childbirth Volume: 21 Issue: 1 Pages: 653-653
  • DOI: 10.1186/s12884-021-04083-y
  • Peer Reviewed / Open Access
• [Journal Article] Atypical preeclampsia with systemic lupus erythematosus and elevated soluble fms‐like tyrosine kinase 1/placental growth factor ratio (2021)
  • Author(s): Mimura Kazuya、Tomimatsu Takuji、Endo Masayuki、Kimura Tadashi
  • Journal Title: Journal of Obstetrics and Gynaecology Research Volume: 47 Issue: 12 Pages: 4461-4466
  • DOI: 10.1111/jog.15055
  • Peer Reviewed
• [Journal Article] Antenatal diagnosis of placenta accreta spectrum after in vitro fertilization-embryo transfer: a systematic review and meta-analysis (2021)
  • Author(s): Matsuzaki Shinya、Nagase Yoshikazu、Takiuchi Tsuyoshi、Kakigano Aiko、Mimura Kazuya、Lee Misooja、Matsuzaki Satoko、Ueda Yutaka、Tomimatsu Takuji、Endo Masayuki、Kimura Tadashi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 9205-9205
  • DOI: 10.1038/s41598-021-88551-7
  • Peer Reviewed / Open Access
• [Journal Article] Reply to the letter to the editor: Conservative management for adherent placenta after live birth in angular or interstitial pregnancies: A new entity “angular placenta attachment” (2021)
  • Author(s): Mimura Kazuya
  • Journal Title: Taiwanese Journal of Obstetrics and Gynecology Volume: 60 Issue: 3 Pages: 584-584
  • DOI: 10.1016/j.tjog.2021.03.041
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis, Management, and Therapy of Fetal Ovarian Cysts Detected by Prenatal Ultrasonography: A Report of 36 Cases and Literature Review (2021)
  • Author(s): Hara Takeya、Mimura Kazuya、Endo Masayuki、Fujii Makoto、Matsuyama Tatsuya、Yagi Kazunobu、Kawanishi Yoko、Tomimatsu Takuji、Kimura Tadashi
  • Journal Title: Diagnostics Volume: 11 Issue: 12 Pages: 2224-2224
  • DOI: 10.3390/diagnostics11122224
  • Peer Reviewed / Open Access
• [Presentation] 【シンポジウム】「妊娠高血圧症候群の管理（産科的な立場から）：HDPの診療指針2021・日産婦GL2023のポイントと今後の改定に向けて」 (2024)
  • Author(s): 味村 和哉
  • Organizer: 第33回腎と妊娠研究会学術集会
  • Invited
• [Presentation] Global panel on Clinical Challenges in Preeclampsia (2023)
  • Author(s): Mimura K
  • Organizer: ISSHP WORLD CONGRESS 2023.
  • Int'l Joint Research
• [Presentation] Severe preeclampsia and HELLP syndrome requiring plasmapheresis or dialysis: National survey in Japan (2023)
  • Author(s): Mimura K, Komatsu R, Endo M, Kimura T
  • Organizer: ISSHP WORLD CONGRESS 2023.
  • Int'l Joint Research
• [Presentation] History of IgA vasculitis with nephropathy (Henoch-Schonlein purpura nephritis) can be a strong risk factor for preeclampsia. (2023)
  • Author(s): Wakui N, Mimura K, Kin S, Funatsu E, Tabuse M, Machimura S, Komatsu R, Okada A, Namakura H, Endo M, Kimura T
  • Organizer: ISSHP WORLD CONGRESS 2023.
  • Int'l Joint Research
• [Presentation] 【教育講演】妊娠関連TMAの診断・治療のポイント HELLP症候群と補体介在性TMA(aHUS) (2023)
  • Author(s): 味村 和哉
  • Organizer: 第75回中国四国産科婦人科総会ならびに学術講演会
  • Invited
• [Presentation] 妊娠18週に発症した重症妊娠高血圧症候群を契機に発見された胎児3倍体の一例 (2022)
  • Author(s): 林田はるえ, 中村幸司, 角田守, 三宅達也, 平松宏祐, 味村和哉, 遠藤誠之,木村正.
  • Organizer: 第58回日本周産期・新生児医学会学術集会
• [Presentation] PIGFに基づくHDPの治療戦略 (2021)
  • Author(s): 味村和哉、冨松拓治、八木一暢、松山達也、中村仁美、木村正
  • Organizer: 日本妊娠高血圧学会第41回学術集会
  • Invited
• [Presentation] FGR症例に対する分娩誘発時のオキシトシン使用についての後方視的検討 (2021)
  • Author(s): 祝 小百合、味村 和哉、遠藤 誠之、川西 陽子、三宅 達也、冨松 拓治、木村 正
  • Organizer: 第145回近畿産科婦人科学会学術集会
• [Presentation] 当院における高安動脈炎合併妊娠8症例の周産期・新生児予後に関する検討 (2021)
  • Author(s): 手向 麻衣、三宅 達也、川西 陽子、前中 隆秀、平松 宏祐、味村 和哉、遠藤 誠之、木村 正
  • Organizer: 第57回日本周産期・新生児医学会学術集会
• [Presentation] 計画分娩中に急激な凝固異常を合併するHELLP症候群を発症した1例 (2021)
  • Author(s): 折出 唯志、川西 陽子、平松 宏裕、前中 隆秀、戸田 有朱香、三宅 達也、中村 幸司、味村 和哉、木村 敏啓、木村 正
  • Organizer: 第144回日本周産期・新生児医学会総会ならびに学術集会
• [Presentation] 膀胱浸潤を疑う前置癒着胎盤に対する緊急帝王切開術の出血コントロールにREBOAが著効した1例 (2021)
  • Author(s): 金光 麻衣、中村 幸司、川西 陽子、前中 隆秀、戸田 有朱香、三宅 達也、平松 宏祐、味村 和哉、木村 敏啓、遠藤 誠之、木村 正
  • Organizer: 第144回日本周産期・新生児医学会総会ならびに学術集会
• [Book] 【産婦人科漢方医学-基礎と臨床のエビデンス-】基礎研究における漢方のエビデンス 妊娠高血圧腎症に対する当帰芍薬散の効果産 婦人科の実際(0558-4728) (2023.03) (2023)
  • Author(s): 八木 一暢(堺市立病院機構堺市立総合医療センター 産婦人科), 味村 和哉
  • Total Pages: 6
  • Publisher: 金原出版
• [Book] 【いま一番新しい妊娠高血圧症候群の助産ケア 妊娠中、分娩～産褥期、退院後の時期別におさえる生理学&ケーススタディ】《妊娠中》入院管理ペリネイタルケア(0910-8718) (2023.07) (2023)
  • Author(s): 小松 伶奈(大阪大学 大学院医学系研究科産科学婦人科学教室), 味村 和哉
  • Total Pages: 5
  • Publisher: メディカ出版
• [Book] 周産期のガイドライン深掘りドリル200問 (2021)
  • Author(s): 遠藤 誠之,味村 和哉 他
  • Total Pages: 256
  • Publisher: メディカ出版
  • ISBN: 9784840472883