The role of lysosomal proteases in podocytes

• Project/Area Number: 24790856
• 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, 非常勤助教 (80599895)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ポドサイト / オートファジー / カテプシンL / カテプシンD / カテプシンＬ / 糸球体硬化 / 蛋白尿

Outline of Final Research Achievements

Injury and loss of podocytes are major risk factors for renal failure. In this study, we aim to investigate the role of lysosomal proteases, cathepsin L (CL) and D (CD) in podocytes. Previous studies showed that up-regulated CL in podocytes is required for the development of proteinuria in mice. We examined the doxorubicin induced nephrosis and glomerulosclerosis model on CL knockout mice.　Our findings suggested that CL-mediated proteolysis plays a role in the development of glomerulosclerosis. The role of CD in podocytes has not been previously explored. We generated podocyte-specific CD knockout mice. These mice developed proteinuria and glomerulosclerosis because of the presence of lysosomal storage disease that progressively worsens with aging. We also discovered that CD deficiency in podocytes leads to apoptotic cell death.
This strongly indicates that CL and CD enzymatic activity in podocytes is generally essential for protein turnover and autophagy homeostasis.

Research Products

• [Journal Article] Combination therapy with telmisartan and oxacalcitriol suppresses the progression of murine adriamycin nephropathy. (2015)
  • Author(s): Jeong KH, Asanuma K, Lydia A, Takagi M, Asao R, Kodama F, Asanuma E, Tomino Y.
  • Journal Title: Nephron Volume: 129(2) Issue: 2 Pages: 143-154
  • DOI: 10.1159/000369346
  • Peer Reviewed / Open Access
• [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] Notch2 activation ameliorates nephrosis. (2014)
  • Author(s): Tanaka E, Asanuma K, Kim E, Sasaki Y, Oliva Trejo JA, Seki T, Nonaka K, Asao R, Nagai-Hosoe Y, Akiba-Takagi M, Hidaka T, Takagi M, Koyanagi A, Mizutani S, Yagita H, Tomino Y.
  • Journal Title: Nature communications Volume: 5 Issue: 1 Pages: 3296-3296
  • DOI: 10.1038/ncomms4296
  • Peer Reviewed / Open Access
• [Journal Article] Transient increase in proteinuria, poly-ubiquitylated proteins and ER stress markers in podocyte-specific autophagy-deficient mice following unilateral nephrectomy. (2014)
  • Author(s): Oliva Trejo JA, Asanuma K, Kim EH, Takagi-Akiba M, Nonaka K, Hidaka T, Komatsu M, Tada N, Ueno T, Tomino Y.
  • Journal Title: Biochemical and biophysical research communications Volume: 446(4) Issue: 4 Pages: 1190-1196
  • DOI: 10.1016/j.bbrc.2014.03.088
  • Peer Reviewed / Open Access
• [Journal Article] Translocation of dendrin to the podocyte nucleus in acute glomerular injury in patients with IgA nephropathy. (2013)
  • Author(s): Kodama F, Asanuma K, Takagi M, Hidaka T, Asanuma E, Fukuda H, Seki T, Takeda Y, Hosoe-Nagai Y, Asao R, Horikoshi S, Tomino Y.
  • Journal Title: Nephrology Dialysis Transplantation. Volume: 28 Issue: 7 Pages: 1762-1772
  • DOI: 10.1093/ndt/gfs500
  • Peer Reviewed
• [Journal Article] Translocation of dendrin to the podocyte nucleus in acute glomerular injury in patients with IgA nephropathy. (2013)
  • Author(s): Kodama F, Asanuma K, Takagi M, Hidaka T, Asanuma E, Fukuda H, Seki T, Takeda Y, Hosoe-Nagai Y, Asao R, Horikoshi S, Tomino Y.
  • Journal Title: Nephrol Dial Transplant. Volume: 28(7) Pages: 1762-1772
  • Peer Reviewed
• [Journal Article] Clinical nephrology 糸球体障害 足細胞障害とオートファジー (2013)
  • Author(s): 淺沼克彦, 日高輝夫, 高木美幸, 富野康日己
  • Journal Title: Annual Review腎臓 Volume: 2013 Pages: 165-171
• [Journal Article] Relationships between levels of urinary podocalyxin, number of urinary podocytes, and histologic injury in adult patients with IgA nephropathy. (2012)
  • Author(s): Asao R, Asanuma K, Kodama F, Akiba-Takagi M, Nagai-Hosoe Y, Seki T, Takeda Y, Ohsawa I, Mano S, Matsuoka K, Kurosawa H, Ogasawara S, Hirayama Y, Sekine S, Horikoshi S, Hara M, Tomino Y.
  • Journal Title: Clin J Am Soc Nephrol. Volume: 7(9) Issue: 9 Pages: 1385-1393
  • DOI: 10.2215/cjn.08110811
  • Peer Reviewed
• [Presentation] RIL(Reversion-induced LIM protein)のポドサイトにおける機能の検討 (2014)
  • Author(s): 田中 絵里子, 淺沼 克彦, 児玉 史子, 高木 美幸, 日高 輝夫, Peter Mundel, 水谷 修紀, 富野 康日己
  • Organizer: 日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
  • Year and Date: 2014-07-04 – 2014-07-06
• [Presentation] Notch2アゴニスト抗体による糸球体硬化改善効果の検討 (2013)
  • Author(s): 田中 絵里子, 淺沼 克彦, 佐々木 有, 関 卓人, Alejandro Oliva Trejo Juan, 野中 香苗, 浅尾 りん, 細江 佳子, 日高 輝夫, 水谷 修紀, 八木田 秀雄, 富野 康日己
  • Organizer: 第56回日本腎臓学会学術総会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] ポドサイト障害におけるNotch再活性化とreceptor特異的糸球体硬化抑制機能の検討.
  • Author(s): 田中絵里子, 淺沼克彦, 関卓人, 野中香苗, 浅尾りん, 細江佳子, 高木美幸, 水谷修紀, 八木田秀雄, 富野康日己.
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Effects of 22-oxa-calcitriol on podocyte injury in adriamycin-induced nephrosis.
  • Author(s): Lidia Aida, 淺沼克彦, 野中香苗, 高木美幸, 富野康日己.
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Relationship between Urinary Podocalyxin Level and Histological Activity in Patients with IgA Nephropathy.
  • Author(s): Rin Asao, Katsuhiko Asanuma, Miyuki Takagi, Hiroyuki Kurosawa, Shinya Ogasawara, Yoshiaki Hirayama, Satoshi, Sakari Sekine, Satoshi Horikoshi, Masanori Hara, Yasuhiko Tomino.
  • Organizer: The 9th international podocyte conference
  • Place of Presentation: マイアミ
• [Presentation] Notch2 pathway reactivation ameliorates urinary protein and glomerular sclerosis in adriamycin nephropathy mice.
  • Author(s): Eriko Tanaka, Katsuhiko Asanuma, Kanae Nonaka, Takuto Seki, Rin Asao, Yoshiko Hosoe, Miyuki Takagi, Alejandro Oliva, Shuki Mizutani, Hideo Yagita, Yasuhiko Tomino.
  • Organizer: The 9th international podocyte conference
  • Place of Presentation: マイアミ