Research into the relationship between autophagy lysosome degradation factors and glomerulosclerosis leading to development of new medical treatment options.

• Project/Area Number: 15K19466
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Juntendo University
• Principal Investigator: TAKAGI Miyuki 順天堂大学, 医学部, 特任助教 (80599895)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: ポドサイト / カテプシンD / カテプシンL / オートファジーリソソーム分解系 / 糸球体硬化 / カテプシン / ネフローゼ / シナプトポディン / ポドサイト剥離 / Sal1 / 細胞骨格 / Rac1 / アドリアマイシン / オートファジー / ポドシン / エンドサイトーシス / 蛋白尿

Outline of Final Research Achievements

The autophagy lysosome degradation system is essential for keeping cell homeostasis. In this study, we investigated the relationship between lysosomal proteases and glomerulosclerosis by focusing especially on cathepsins D (CD) and L (CL) in podocytes.
We analyzed podocyte specific CD knockout mice and found that CD deficiency results in dysregulation of podocyte function. Moreover, we examined the role of CL in rat podocytes using a Puromycin Aminonucleoside (PAN) nephrosis model. We discovered that CL levels and the absence of its inhibitors in podocytes affected by PAN nephrosis, are important factors contributing to podocyte damage and the development of proteinuria.Together, our results indicate that CD and CL activity are essential for quality control in podocytes.

Academic Significance and Societal Importance of the Research Achievements

オートファジー・リソソーム経路による分解系関連蛋白と糸球体硬化進展メカニズムの病態の解明は、特に蛋白分解系に着目した創薬研究にも密接に関連すると考える。
また、糸球体硬化進展メカニズムの関係解明により、ポドサイト障害のバイオマーカーの検出にもつながり、さらには糸球体硬化・慢性腎臓病を減らすことが出来るような治療薬の開発への糸口となりうる。

Research Products

• [Journal Article] Neurofilament heavy polypeptide protects against reduction in synaptopodin expression and prevents podocyte detachment (2018)
  • Author(s): Wang Juan、Hidaka Teruo、Sasaki Yu、Tanaka Eriko、Takagi Miyuki、Shibata Terumi、Kubo Ayano、Trejo Juan Alejandro Oliva、Wang Lining、Asanuma Katsuhiko、Tomino Yasuhiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 17157-17171
  • DOI: 10.1038/s41598-018-35465-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of Cathepsin L and Its Intrinsic Inhibitors in Glomeruli of Rats With Puromycin Aminonucleoside Nephrosis (2018)
  • Author(s): Kubo Ayano、Shirato Isao、Hidaka Teruo、Takagi Miyuki、Sasaki Yu、Asanuma Katsuhiko、Ishidoh Kazumi、Suzuki Yusuke
  • Journal Title: Journal of Histochemistry & Cytochemistry Volume: 66 Issue: 12 Pages: 863-877
  • DOI: 10.1369/0022155418791822
  • Peer Reviewed
• [Journal Article] Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis (2018)
  • Author(s): Asao Rin、Seki Takuto、Takagi Miyuki、Yamada Hiroyuki、Kodama Fumiko、Hosoe-Nagai Yoshiko、Tanaka Eriko、Trejo Juan Alejandro Oliva、Yamamoto-Nonaka Kanae、Sasaki Yu、Hidaka Teruo、Ueno Takashi、Yanagita Motoko、Suzuki Yusuke、Tomino Yasuhiko、Asanuma Katsuhiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 5061-5061
  • DOI: 10.1038/s41598-018-23278-6
  • NAID: 120006517798
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Re-expression of Sall1 in podocytes protects against adriamycin-induced nephrosis (2017)
  • Author(s): Hosoe-Nagai Yoshiko、Hidaka Teruo、Sonoda Ayano、Sasaki Yu、Yamamoto-Nonaka Kanae、Seki Takuto、Asao Rin、Tanaka Eriko、Trejo Juan Alejandro Oliva、Kodama Fumiko、Takagi Miyuki、Tada Nobuhiro、Ueno Takashi、Nishinakamura Ryuichi、Tomino Yasuhiko、Asanuma Katsuhiko
  • Journal Title: Laboratory Investigation Volume: 97 Issue: 11 Pages: 1306-1320
  • DOI: 10.1038/labinvest.2017.69
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sorting Nexin 9 facilitates podocin endocytosis in the injured podocyte. (2017)
  • Author(s): Sasaki Y, Hidaka T, Ueno T, Akiba-Takagi M, Trejo JA, Seki T, Nagai-Hosoe Y, Tanaka E, Horikoshi S, Tomino Y, Suzuki Y, Asanuma K.
  • Journal Title: 10.1038/srep43921.2017 Volume: 7 Issue: 1 Pages: 43921-43921
  • DOI: 10.1038/srep43921
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Cathepsin D in Podocytes Is Important in the Pathogenesis of Proteinuria and CKD (2016)
  • Author(s): Yamamoto-Nonaka K, Koike M, Asanuma K, Takagi M, Oliva Trejo JA, Seki T, Hidaka T, Ichimura K, Sakai T, Tada N, Ueno T, Uchiyama Y, Tomino Y
  • Journal Title: jornal of American Society of Nephrology Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Podocin is translocated to cytoplasm in puromycin aminonucleoside nephrosis rats and in poor-prognosis patients with IgA nephropathy. (2015)
  • Author(s): Fukuda H, Hidaka T, Takagi-Akiba M, Ichimura K, Trejo JA, Sasaki Y, Wang J, Sakai T, Asanuma K, Tomino Y.
  • Journal Title: Cell & Tissue Research Volume: 360(2) Issue: 2 Pages: 391-400
  • DOI: 10.1007/s00441-014-2100-9
  • Peer Reviewed / Open Access
• [Journal Article] Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice (2015)
  • Author(s): Masanori Ishizaka, Tomohito Gohda, Miyuki Takagi, Keisuke Omote, Yuji Sonoda, Juan Alejandro Oliva Trejo, Rin Asao, Teruo Hidaka, Katsuhiko Asanuma, Satoshi Horikoshi, Yasuhiko Tomino
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 467 Issue: 3 Pages: 549-555
  • DOI: 10.1016/j.bbrc.2015.09.158
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Newly identified molecules related to podocyte injury induced by Adriamycin (2015)
  • Author(s): Wang J, Asanuma K, Hidaka T, Sasaki Y, Tanaka E, Takagi-Akiba E, Oliva Trejo J.A, and Tomino Y
  • Journal Title: Juntendo Medical Journal Volume: 61 Pages: 34-40
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Toll-like receptor 8 and 10 are possibly associated with pathogenic mechanisms of idiopathic nephrotic syndrome. (2017)
  • Author(s): Eriko Tanaka and Miyuki Takagi
  • Organizer: American Society of Nephrology Kidney Week 2017
  • Int'l Joint Research