Evaluation of cardiorenal syndrome in progression of chronic kidney disease

• Project/Area Number: 20K08633
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Kyoto University
• Principal Investigator: Yokoi Hideki 京都大学, 医学研究科, 講師 (90378779)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 心腎連関 / 慢性心不全 / 急性腎障害 / 虚血再灌流障害 / 虚血再灌流 / 心不全 / ポドサイト / ナトリウム利尿ペプチド / 一側尿管結紮 / 腎不全

Outline of Research at the Start

近年、心臓と腎臓の生理学的・病理学的な密接な関係性を「心腎連関」と呼称し、包括的な病態理解・治療介入探索が検討されるようになってきている。心臓・腎臓の一方に生じた障害が、他方にも影響して障害を引きおこすcardio-renal syndrome (CRS)という疾患概念も広く受け入れられている。本研究は心不全マウスを用いて、そのマウスに腎障害を起こすことにより心腎連関の機序を解明する研究である。

Outline of Final Research Achievements

In this study, we performed ischemia-reperfusion of the renal arteries after unilateral nephrectomy in dnNRSF-Tg heart failure mice in order to elucidate the molecular mechanism of the cardio-renal connection. Serum Cr and serum BUN were significantly elevated in heart failure mice compared to wild-type mice, indicating that renal function was aggravated in heart failure mice. Moreover, in heart failure mice, increased expression of Ccl2 and Lcn2 was observed in total renal RNA, suggesting enhanced inflammation and tubular damage. These results indicate that renal function worsens with exacerbation of inflammatory reaction when renal injury develops in heart failure.In addition, we performed microarray study showing the elevation of Psma1, Lrit1, and Sdr16c6 expression in the whole kidney.

Academic Significance and Societal Importance of the Research Achievements

慢性心不全がある患者さんは腎機能が悪いことが多く、また心不全の増悪時には腎機能も悪化することが分かっていました。本研究は心不全状態の場合に、腎動脈を一時的に阻血し再灌流することにより腎臓に障害を与えるモデルを使用して、腎機能がなぜ悪くなるのかについての機序解明を目的とした研究です。本研究の成果により、心不全患者の腎機能を早期に発見するマーカーの検出や、機序解明により腎機能悪化防止できる治療法の開発につなげることを目標としています。

Research Products

• [Journal Article] STAT3 is Activated by CTGF-mediated Tumor-stroma Cross Talk to Promote HCC Progression (2023)
  • Author(s): Makino Yuki、Hikita Hayato、Kato Seiya、Sugiyama Masaya、Shigekawa Minoru、Sakamoto Tatsuya、Sasaki Yoichi、Murai Kazuhiro、Sakane Sadatsugu、Kodama Takahiro、Sakamori Ryotaro、Kobayashi Shogo、Eguchi Hidetoshi、Takemura Nobuyuki、Kokudo Norihiro、Yokoi Hideki、Mukoyama Masashi、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 15 Issue: 1 Pages: 99-119
  • DOI: 10.1016/j.jcmgh.2022.09.006
  • Peer Reviewed
• [Journal Article] Inhibition of mitochondrial fission protects podocytes from albumin-induced cell damage in diabetic kidney disease (2022)
  • Author(s): Tagaya Makoto、Kume Shinji、Yasuda-Yamahara Mako、Kuwagata Shogo、Yamahara Kosuke、Takeda Naoko、Tanaka Yuki、Chin-Kanasaki Masami、Nakae Yuki、Yokoi Hideki、Mukoyama Masashi、Ishihara Naotada、Nomura Masatoshi、Araki Shin-ichi、Maegawa Hiroshi
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Volume: 1868 Issue: 5 Pages: 166368-166368
  • DOI: 10.1016/j.bbadis.2022.166368
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Osteocrin ameliorates adriamycin nephropathy via p38 mitogen-activated protein kinase inhibition (2021)
  • Author(s): Handa Takaya、Mori Keita P.、Ishii Akira、Ohno Shoko、Kanai Yugo、Watanabe-Takano Haruko、Yasoda Akihiro、Kuwabara Takashige、Takahashi Nobuyuki、Mochizuki Naoki、Mukoyama Masashi、Yanagita Motoko、Yokoi Hideki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 21835-21835
  • DOI: 10.1038/s41598-021-01095-8
  • Peer Reviewed / Open Access
• [Journal Article] Osteocrin, a bone-derived humoral factor, exerts a renoprotective role in ischemia-reperfusion injury in mice (2021)
  • Author(s): Nishiguchi Yoshihiko、Hata Yusuke、Date Ryosuke、Fujimoto Daisuke、Umemoto Shuro、Kanki Tomoko、Yokoi Hideki、Mori Keita P、Handa Takaya、Watanabe-Takano Haruko、Kanai Yugo、Yasoda Akihiro、Izumi Yuichiro、Kakizoe Yutaka、Mochizuki Naoki、Mukoyama Masashi、Kuwabara Takashige
  • Journal Title: Nephrology Dialysis Transplantation Volume: 37 Issue: 3 Pages: 444-453
  • DOI: 10.1093/ndt/gfab286
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Kidney Histological Images Using Unsupervised Deep Learning (2021)
  • Author(s): Sato Noriaki、Uchino Eiichiro、Kojima Ryosuke、Sakuragi Minoru、Hiragi Shusuke、Minamiguchi Sachiko、Haga Hironori、Yokoi Hideki、Yanagita Motoko、Okuno Yasushi
  • Journal Title: Kidney International Reports Volume: 6 Issue: 9 Pages: 2445-2454
  • DOI: 10.1016/j.ekir.2021.06.008
  • Peer Reviewed / Open Access
• [Journal Article] Dysregulation of PI3K and Hippo signaling pathways synergistically induces chronic pancreatitis via CTGF upregulation (2021)
  • Author(s): Tamura Takeshi、Kodama Takahiro、Sato Katsuhiko、Murai Kazuhiro、Yoshioka Teppei、Shigekawa Minoru、Yamada Ryoko、Hikita Hayato、Sakamori Ryotaro、Akita Hirofumi、Eguchi Hidetoshi、Johnson Randy L.、Yokoi Hideki、Mukoyama Masashi、Tatsumi Tomohide、Takehara Tetsuo
  • Journal Title: Journal of Clinical Investigation Volume: 131 Issue: 13
  • DOI: 10.1172/jci143414
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MAGI-2 orchestrates the localization of backbone proteins in the slit diaphragm of podocytes (2021)
  • Author(s): Yamada Hiroyuki, Mukoyama Masashi, Asanuma Katsuhiko, et al.
  • Journal Title: Kidney International Volume: 99 Issue: 2 Pages: 382-395
  • DOI: 10.1016/j.kint.2020.09.027
  • Peer Reviewed / Open Access
• [Journal Article] Mice lacking core 1-derived O-glycan in podocytes develop transient proteinuria, resulting in focal segmental glomerulosclerosis (2020)
  • Author(s): Fuseya Sayaka、Suzuki Riku、Okada Risa、Hagiwara Kozue、Sato Takashi、Narimatsu Hisashi、Yokoi Hideki、Kasahara Masato、Usui Toshiaki、Morito Naoki、Yamagata Kunihiro、Kudo Takashi、Takahashi Satoru
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 523 Issue: 4 Pages: 1007-1013
  • DOI: 10.1016/j.bbrc.2020.01.033
  • Peer Reviewed
• [Journal Article] Ablation of Myeloid Cell MRP8 Ameliorates Nephrotoxic Serum-induced Glomerulonephritis by Affecting Macrophage Characterization through Intraglomerular Crosstalk (2020)
  • Author(s): Hata Yusuke、Kuwabara Takashige、Mori Kiyoshi、Kan Youngna、Sato Yuki、Umemoto Shuro、Fujimoto Daisuke、Kanki Tomoko、Nishiguchi Yoshihiko、Yokoi Hideki、Kakizoe Yutaka、Izumi Yuichiro、Yanagita Motoko、Mukoyama Masashi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 3056-3056
  • DOI: 10.1038/s41598-020-59970-9
  • NAID: 120006956435
  • Peer Reviewed / Open Access
• [Journal Article] Pivotal role of podocyte autophagy against glomerular endothelial dysfunction in diabetes. (2020)
  • Author(s): Yoshibayashi M, Kume S, Yasuda-Yamahara M, Yamahara K, Takeda N, Osawa N, Chin-Kanasaki M, Nakae Y, Yokoi H, Mukoyama M, Asanuma K, Maegawa H, Araki SI.
  • Journal Title: Biochem Biophys Res Commun. Volume: 525 Issue: 2 Pages: 319-325
  • DOI: 10.1016/j.bbrc.2020.02.088
  • Peer Reviewed / Open Access
• [Journal Article] Transcription factor MafB in podocytes protects against the development of focal segmental glomerulosclerosis. (2020)
  • Author(s): Usui T, Morito N, Shawki HH, Sato Y, Tsukaguchi H, (20人略）, Takahashi S.
  • Journal Title: Kidney International Volume: in press Issue: 2 Pages: 391-403
  • DOI: 10.1016/j.kint.2020.02.038
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Classification of glomerular pathological findings using deep learning and nephrologist?AI collective intelligence approach (2020)
  • Author(s): Uchino Eiichiro、Suzuki Kanata、Sato Noriaki、Kojima Ryosuke、Tamada Yoshinori、Hiragi Shusuke、Yokoi Hideki、Yugami Nobuhiro、Minamiguchi Sachiko、Haga Hironori、Yanagita Motoko、Okuno Yasushi
  • Journal Title: International Journal of Medical Informatics Volume: 141 Pages: 104231-104231
  • DOI: 10.1016/j.ijmedinf.2020.104231
  • Peer Reviewed
• [Journal Article] Proteolytic cleavage of Podocin by Matriptase exacerbates podocyte injury (2020)
  • Author(s): Ozawa Shota、Matsubayashi Masaya、Nanaura Hitoki、Yanagita Motoko、Mori Kiyoshi、Asanuma Katsuhiko、Kajiwara Nobuyuki、Hayashi Kazuyuki、Ohashi Hiroshi、Kasahara Masato、Yokoi Hideki、Kataoka Hiroaki、Mori Eiichiro、Nakagawa Takahiko
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 47 Pages: 16002-16012
  • DOI: 10.1074/jbc.ra120.013721
  • Peer Reviewed / Open Access
• [Presentation] オステオクリンはナトリウム利尿ペプチド受容体3を阻害し、アドリアマイシン腎症 を軽減する (2022)
  • Author(s): 半田貴也，森 慶太，石井 輝，大野祥子，金井有吾，八十田明宏，桒原孝成，向山政志，柳田素子，横井秀基
  • Organizer: 第65回日本腎臓内科学会総会
• [Presentation] ポドサイト特異的p38 MAPK&GC-Aダブルノックアウトマウスの腎病変におけるポドサイトー内皮連関の解明 (2022)
  • Author(s): 杉岡清香，山田博之，加藤有希子，石井 輝，森 慶太，大崎啓介，徳留 健，松阪泰二， 柳田素子，横井秀基
  • Organizer: 第65回日本腎臓内科学会総会
• [Presentation] 拡張型心筋症モデルマウスを用いた心腎連関の機序解明 (2022)
  • Author(s): 石村拓也，石井 輝，山田博之，中川靖章，大野祥子，生島昭恵，杉岡清香，半田貴也，桑原:宏一郎，柳田素子，横井秀基
  • Organizer: 第65回日本腎臓内科学会総会
• [Presentation] Matrix metalloproteinase-10欠損マウスにおける腹膜の炎症・線維化の抑制効果の検討 (2021)
  • Author(s): 石村拓也，石井 輝，大崎啓介，戸田尚宏，森 慶太，半田貴也，柳田素子，横井秀基
  • Organizer: 第64回日本腎臓学会学術総会
• [Presentation] ポドサイト特異的p38 MAPK欠損はアルドステロン投与GC-Aノックアウトマウスの 糸球体障害を悪化させる (2021)
  • Author(s): 杉岡清香，山田博之，石井 輝，加藤有希子，森 慶太，大崎啓介，徳留 健，松阪泰二， 柳田素子，横井秀基
  • Organizer: 第64回日本腎臓学会学術総会
• [Presentation] オステオクリンはNPR1signalを促進し、リン酸化p38を抑制することで足細胞に保護 的に作用する (2021)
  • Author(s): 半田貴也，森 慶太，石井 輝，金井有吾，八十田明宏，桒原孝成，向山政志，柳田素子，横井秀基
  • Organizer: 第64回日本腎臓学会学術総会
• [Presentation] Role of Matrix Metalloproteinase-10 in Macrophages and Peritoneal Fibrosis (2021)
  • Author(s): 石村拓也，石井 輝，大崎啓介，戸田尚宏，森 慶太，半田貴也，柳田素子，横井秀基
  • Organizer: 第27回日本腹膜透析医学会学術集会・総会
• [Presentation] オステオクリンはP38MAPKのリン酸化抑制を介してアドリアマイシン腎症を改善する (2020)
  • Author(s): 半田貴也，森慶太，石井輝，大野祥子，金井有吾，八十田明宏，桒原孝成，向山政志，柳田素子，横井秀基
  • Organizer: 第63回日本腎臓学会学術総会
• [Presentation] アルドステロン誘導性糸球体障害に対する足細胞のp38 MAPK欠失の影響 (2020)
  • Author(s): 杉岡清香，加藤有希子，石井輝，森慶太，大﨑啓介，徳留健， 松阪泰二，柳田素子，横井秀基
  • Organizer: 第63回日本腎臓学会学術総会
• [Presentation] MMP-10欠損による抗GBM腎炎の改善 (2020)
  • Author(s): 大﨑啓介，加藤有希子，石井輝，森慶太，森潔，笠原正登，向山政志，柳田素子，横井秀基
  • Organizer: 第63回日本腎臓学会学術総会
• [Remarks] 京都大学大学院医学研究科腎臓内科学
  • URL: https://www.kidney-kyoto-u.jp/
• [Remarks] 京都大学大学院医学研究科 腎臓内科学
  • URL: https://www.kidney-kyoto-u.jp/