Elucidation of the mechanism of podocyte damage in chronic kidney disease by focusing on lysosomal damage

• Project/Area Number: 18K15998
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Yasuda-Yamahara Mako 滋賀医科大学, 医学部, 特任講師 (70731941)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 慢性腎臓病 / ポドサイト / リソソーム / CKD / 糸球体上皮細胞

Outline of Final Research Achievements

The number of patients with chronic kidney disease (CKD) in Japan is increasing, and elucidating the pathogenesis of CKD is an important research issue. Proteinuria, which is a diagnostic criterion for CKD, is mainly caused by podocyte injury, and maintaining intracellular homeostasis is important for podocytes, which do not have the ability to divide and regenerate. In this study, we hypothesized that the enhancement of lysosome function, which is responsible for intracellular proteolysis, would act cytoprotectively against podocyte injury in CKD. We found that activation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, suppressed podocyte damage. This suggests that inhibition of podocyte damage through TFEB-mediated activation of lysosomal biogenesis may be a new therapeutic strategy for CKD.

Academic Significance and Societal Importance of the Research Achievements

わが国の慢性腎臓病（CKD）患者数は増加の一途を辿っている。CKDとは糸球体濾過量の低下、蛋白尿の持続により定義される疾患群で、その病態は多種多様である。しかし、蛋白尿の主な原因となるのは糸球体スリット膜を形成するポドサイトの障害であり、この障害を抑制する機構を解明すれば、すなわち多くのCKD患者にとっての新たな治療法の開発につながると考えられる。今回、分裂能を有さないポドサイトにおいて、細胞内の蛋白分解を担うリソソームの転写因子TFEB活性化による細胞保護効果が明らかとなった。TFEBによるリソソームの活性化を介したポドサイト障害の抑制がCKDの新たな治療戦略になり得る可能性が示唆された。

Research Products

• [Journal Article] Roles of mTOR in Diabetic Kidney Disease (2021)
  • Author(s): Yasuda-Yamahara M, Kume S, Maegawa H.
  • Journal Title: Antioxidants Volume: 10 Issue: 2 Pages: 321-321
  • DOI: 10.3390/antiox10020321
  • NAID: 120006979532
  • Peer Reviewed / Open Access
• [Journal Article] SRGAP1 controls small Rho GTPases to regulate podocyte foot process maintenance. (2021)
  • Author(s): Rogg M, Maier JI, Dotzauer R, Artelt N, Kretz O, Helmstaedter M, Abed A, Sammarco A, Sigle A, Sellung D, Dinse P, Reiche K, Yasuda-Yamahara M, Biniossek ML, Walz G, Werner M, Endlich N, Schilling O, Huber TB, Schell C
  • Journal Title: J Am Soc Nephrol Volume: 32 Issue: 3 Pages: 563-579
  • DOI: 10.1681/asn.2020081126
  • Peer Reviewed
• [Journal Article] SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition (2020)
  • Author(s): Tomita Issei、Kume Shinji、Sugahara Sho、Osawa Norihisa、Yamahara Kosuke、Yasuda-Yamahara Mako、Takeda Naoko、Chin-Kanasaki Masami、Kaneko Tatsuroh、Mayoux Eric、Mark Michael、Yanagita Motoko、Ogita Hisakazu、Araki Shin-ichi、Maegawa Hiroshi
  • Journal Title: Cell Metabolism Volume: 32 Issue: 3 Pages: 404-404
  • DOI: 10.1016/j.cmet.2020.06.020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes (2019)
  • Author(s): Sugahara S, Kume S, Chin-Kanasaki M, Tomita I, Yasuda-Yamahara M, Yamahara K, Takeda N, Osawa N, Yanagita M, Araki SI, Maegawa H.
  • Journal Title: Journal of the American Society of Nephrology Volume: In press Issue: 6 Pages: 962-978
  • DOI: 10.1681/asn.2018090950
  • Peer Reviewed / Open Access
• [Journal Article] ARP3 controls the podocyte architecture at the kidney filtration barrier. (2018)
  • Author(s): Schell C, Sabass B, Helmstaedter M, Geist F, Abed A, Yasuda-Yamahara M, Sigle A, Maier JI, Grahammer F, Siegerist F, Artelt N, Endlich N, Kerjaschki D, Arnold HH, Dengjel J, Rogg M, Huber TB.
  • Journal Title: Dev Cell. Volume: 47 Issue: 6 Pages: 741-757
  • DOI: 10.1016/j.devcel.2018.11.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] AIF1L regulates actomyosin contractility and filopodial extensions in human podocytes. (2018)
  • Author(s): Yasuda-Yamahara M, Rogg M, Yamahara K, Maier JI, Huber TB, Schell C.
  • Journal Title: PLoS One. Volume: 13 Issue: 7 Pages: e0200487-e0200487
  • DOI: 10.1371/journal.pone.0200487
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Role of dietary amino acid balance in diet restriction-mediated lifespan extension, renoprotection, and muscle weakness in aged mice. (2018)
  • Author(s): Yoshida S, Yamahara K, Kume S, Koya D, Yasuda-Yamahara M, Takeda N, Osawa N, Chin-Kanasaki M, Adachi Y, Nagao K, Maegawa H, Araki SI.
  • Journal Title: Aging Cell. Volume: 17 Issue: 4
  • DOI: 10.1111/acel.12796
  • Peer Reviewed / Open Access
• [Journal Article] FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology (2018)
  • Author(s): Yasuda-Yamahara M.、Rogg M.、Frimmel J.、Trachte P.、Helmstaedter M.、Schroder P.、Schiffer M.、Schell C.、Huber T.B.
  • Journal Title: Matrix Biology Volume: 印刷中 Pages: 30401-30408
  • DOI: 10.1016/j.matbio.2018.01.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Whole-body energy metabolism and podocytopathy. (2020)
  • Author(s): 山原 真子
  • Organizer: 第43回日本分子生物学会年会
• [Presentation] Intracellular nutrient signals and diabetic kidney disease. (2020)
  • Author(s): 山原 真子
  • Organizer: 第63回日本糖尿病学会年次学術集会
• [Presentation] Autophagy protects podocytes from diabetes-related glomerular endothelial damage. (2019)
  • Author(s): Yasuada-Yamahara M, Yoshibayashi M, Kume S, Araki SI, Maegawa H.
  • Organizer: International Diabetes Federation 2019 (IDF 2019)
  • Int'l Joint Research
• [Presentation] 糸球体上皮細胞の接着機構における新規細胞接着分子FERMT2の同定 (2018)
  • Author(s): 山原 真子
  • Organizer: 第61回日本腎臓学会総会学術総会