Role of downstream molecules of natriuretic peptides on podocytes in chronic kidney disease

• Project/Area Number: 17K09697
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Kidney internal medicine
• Research Institution: Kyoto University
• Principal Investigator: YOKOI HIDEKI 京都大学, 医学研究科, 講師 (90378779)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ポドサイト / ナトリウム利尿ペプチド / アルドステロン / 抗糸球体基底膜腎炎 / 内皮細胞 / 蛋白分解酵素 / 糸球体 / 腎 / matrix metalloproteinase / MMP-10 / 高血圧 / 内科 / トランスレーショナルリサーチ / 循環器・高血圧

Outline of Final Research Achievements

I focused on matrixi metalloproteinase-10 (MMP-10) which is increased in glomeruli by deletion of natriuretic peptide receptor. MMMP-10 was increased at the proliferative lesions in the renal biopsy specimen. ALDO, which means aldosterone infusion, heninephrectomy and high salt diet, stimulated systemic GC-A and MMP-10 double knockout (KO) mice exhibited less glomerular injury and albuminuria. In addition, podocyte-specific GC-A KO and MMP-10 KO double KO mice also showed similar results.
In conclusion, inhibition of MMP-10 could be a potential target against renal injury.

Academic Significance and Societal Importance of the Research Achievements

腎障害の程度とMMP-10発現が相関しうるデータは腎疾患においてMMP-10がマーカーとなりうる可能性を示唆している。今後血中や尿中MMP-10が疾患活動性マーカーになりうるか検討が必要である。
また、MMP-10抑制が腎疾患を軽減させる可能性は今後の創薬標的となりうる可能性を示唆している。

Research Products

• [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] Roles of matricellular CCN2 deposited by osteocytes in osteoclastogenesis and osteoblast differentiation (2019)
  • Author(s): Nishida T, Kubota S, Yokoi H, Mukoyama M, Takigawa M
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 10913-10913
  • DOI: 10.1038/s41598-019-47285-3
  • Peer Reviewed / Open Access
• [Journal Article] Connective tissue growth factor is correlated with peritoneal lymphangiogenesis (2019)
  • Author(s): Kinashi Hiroshi、Toda Naohiro、Sun Ting、Nguyen Tri Q.、Suzuki Yasuhiro、Katsuno Takayuki、Yokoi Hideki、Aten Jan、Mizuno Masashi、Maruyama Shoichi、Yanagita Motoko、Goldschmeding Roel、Ito Yasuhiko
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12175-12175
  • DOI: 10.1038/s41598-019-48699-9
  • NAID: 120006958096
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Decreased KAT5 Expression Impairs DNA Repair and Induces Altered DNA Methylation in Kidney Podocytes (2019)
  • Author(s): Hishikawa Akihito、Hayashi Kaori、Abe Takaya、Kaneko Mari、Yokoi Hideki、Azegami Tatsuhiko、Nakamura Mari、Yoshimoto Norifumi、Kanda Takeshi、Sakamaki Yusuke、Itoh Hiroshi
  • Journal Title: Cell Reports Volume: 26 Issue: 5 Pages: 1318-1332
  • DOI: 10.1016/j.celrep.2019.01.005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CTGF in kidney fibrosis and glomerulonephritis (2018)
  • Author(s): Toda Naohiro、Mukoyama Masashi、Yanagita Motoko、Yokoi Hideki
  • Journal Title: Inflammation and Regeneration Volume: 38 Issue: 1 Pages: 14-14
  • DOI: 10.1186/s41232-018-0070-0
  • Peer Reviewed
• [Journal Article] Guanylyl cyclase A in both renal proximal tubular and vascular endothelial cells protects the kidney against acute injury in rodent experimental endotoxemia models. (2018)
  • Author(s): Kidney against Acute Injury in Rodent Experimental Endotoxemia Models. Kitamura H, Nakano D, Sawanobori Y, Asaga T, Yokoi H, Yanagita M, Mukoyama M, Tokudome T, Kangawa K, Shirakami G, Nishiyama A.
  • Journal Title: Anesthesiology Volume: 印刷中 Issue: 2 Pages: 296-310
  • DOI: 10.1097/aln.0000000000002214
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deletion of connective tissue growth factor ameliorates peritoneal fibrosis by inhibiting angiogenesis and inflammation (2017)
  • Author(s): Toda Naohiro、Mori Kiyoshi、Kasahara Masato、Koga Kenichi、Ishii Akira、Mori Keita P、Osaki Keisuke、Mukoyama Masashi、Yanagita Motoko、Yokoi Hideki
  • Journal Title: Nephrology Dialysis Transplantation Volume: - Issue: 6 Pages: 943-953
  • DOI: 10.1093/ndt/gfx317
  • Peer Reviewed / Open Access
• [Journal Article] Obesity-promoting and anti-thermogenic effects of neutrophil gelatinase-associated lipocalin in mice (2017)
  • Author(s): Ishii Akira、Katsuura Goro、Imamaki Hirotaka、Kimura Hiroyuki、Mori Keita P.、Kuwabara Takashige、Kasahara Masato、Yokoi Hideki、Ohinata Kousaku、Kawanishi Tomoko、Tsuchida Junichi、Nakamoto Yuji、Nakao Kazuwa、Yanagita Motoko、Mukoyama Masashi、Mori Kiyoshi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 15501-15501
  • DOI: 10.1038/s41598-017-15825-4
  • Peer Reviewed / Open Access
• [Journal Article] Natriuretic peptide receptor guanylyl cyclase-A pathway counteracts glomerular injury evoked by aldosterone through p38 mitogen-activated protein kinase inhibition. (2017)
  • Author(s): Y. Kato, K. Mori, M. Kasahara, K. Osaki, A. Ishii, K.P. Mori, N. Toda, S. Ohno, T. Kuwabara, T. Tokudome, I. Kishimoto, M.A. Saleem, T. Matsusaka, K. Nakao, M. Mukoyama, M. Yanagita, H. Yokoi
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 46624-46624
  • DOI: 10.1038/srep46624
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Crucial role of mesangial cell-derived connective tissue growth factor in a mouse model of anti-glomerular basement membrane glomerulonephritis. (2017)
  • Author(s): Toda N, Mori K, Kasahara M, Ishii A, Koga K, Ohno S, Mori KP. Kato Y, Osaki K, Kuwabara T, Kojima K, Taura D, Sone M, Matsusaka T, Nakao K, Mukoyama M, Yanagita M, Yokoi H.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 42114-42114
  • DOI: 10.1038/srep42114
  • NAID: 120005997757
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Matrix metalloproteinase-10 is a key molecule in aldosterone-induced glomerular injury in systemic guanylyl cyclase-A knockout mice (2019)
  • Author(s): Yokoi H,Osaki K, Kato Y, Toda N, Ishi A, Mori K P ,Kosaki K ,Kasahara M, Mukoyama M, Yanagita M.
  • Organizer: World Congress of Nephrology 2019
  • Int'l Joint Research
• [Presentation] Evaluation of mechanism on peritoneal fibrosis using genetically modified mice (2019)
  • Author(s): Yokoi H, Ishimura T, Toda N; Yanagita M,
  • Organizer: Asian Pacific Chapter Meeting -International Society for Peritoneal Dialysis 2019
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍崩壊症候群の診断と対策 (2019)
  • Author(s): 横井秀基，柳田素子
  • Organizer: 第62回日本腎臓学会学術総会
  • Invited
• [Presentation] 腹膜透析普及へ向けての導入～大規模PD実施施設から学ぶ～ (2019)
  • Author(s): 横井秀基，柳田素子
  • Organizer: 第64回日本透析医学会学術集会・総会
  • Invited
• [Presentation] アルドステロンによるポドサイト傷害におけるナトリウム利尿ペプチドとp38 MAPKの意義 (2019)
  • Author(s): 横井秀基，加藤有希子，杉岡清香，向山政志，柳田素子
  • Organizer: 第29回日本循環薬理学会・第55回高血圧関連疾患モデル学会
  • Invited
• [Presentation] アルドステロン誘発高血圧腎障害モデルにおけるナトリウム利尿ペプチド系の拮抗作用機序 (2018)
  • Author(s): 横井秀基、大崎啓介、加藤有希子、向山政志、柳田素子
  • Organizer: 第54回高血圧関連疾患モデル学会学術集会
  • Invited
• [Presentation] RAA系抑制因子としてのナトリウム利尿ペプチド系の意義とアルドステロン誘発ポドサイト傷害におけるクロストーク (2018)
  • Author(s): 横井秀基、大崎啓介、加藤有希子、向山政志、柳田素子
  • Organizer: 第41回日本高血圧学会学術集会
  • Invited
• [Presentation] MMP-10欠損によるアルドステロン投与GC-A ノックアウトマウスの腎病変の改善 (2018)
  • Author(s): 大﨑啓介、 加藤有希子、 戸田尚宏、 石井輝 森 潔、松阪泰二、向山政志、柳田素子、横井秀基
  • Organizer: 第61回日本腎臓学会
• [Presentation] Deletion of matrix metalloproteinase-10 ameliorates aldosterone-induced glomerular injury in guanylyl cyclase-A knockout mice (2018)
  • Author(s): Osaki K, Kato Y, Toda N, Ishi A, Mori K P,Ohno S, Mori K, Kasahara M, Mukoyama M, Yanagita M, Yokoi H
  • Organizer: Annual Meeting of American Society of Nephrology
  • Int'l Joint Research
• [Presentation] Upregulation of Matrix Metalloproteinase-10 in Glomerular Cells and Macrophages by Inflammation (2017)
  • Author(s): Osaki K, Kato Y, Toda N, Ishii A, Keita P. Mori K P, Ohno S, Mori K, Moin A. Saleem, Matsusaka T, Mukoyama M, Yanagita M, Yokoi H.
  • Organizer: American Society of Nephrology Annual Meeting
  • Int'l Joint Research
• [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 腎臓内科学講座
  • URL: http://www.kidney.kuhp.kyoto-u.ac.jp/