Investigation of the mechanism underlying urinary excretion of megalin, a novel biomarker of diabetic kidney disease

• Project/Area Number: 26860630
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Kidney internal medicine
• Research Institution: Niigata University
• Principal Investigator: Hosojima Michihiro 新潟大学, 医歯学総合研究科, 特任准教授 (50464003)
• Research Collaborator: DE Shankhajit ; KUWAHARA Shoji (70645209) ; KABASAWA Hideyuki (20794639) ; SAITO Akihiko (80293207)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 糖尿病性腎症 / バイオマーカー / メガリン / 近位尿細管 / エクソソーム / 尿中バイオマーカー

Outline of Final Research Achievements

I studied the mechanism underlying urinary excretion of megalin, a multiligand endocytic receptor in the proximal tubules, in diabetic kidney disease (DKD). Urinary extracellular vesicle (UEV) excretion and full-length megalin (C-megalin) content in UEVs or in their exosomal fraction increased along with the progression of the albuminuric stages in patients with type 2 diabetes mellitus (T2DM). C-megalin excretion from cultured immortalized rat proximal tubule cells via extracellular vesicles was increased via lysosomal dysfunction in association with megalin-mediated cellular uptake of advanced glycation endproducts, which is significantly blocked by an exosome-specific inhibitor, GW4869. In a high-fat diet-induced, megalin-mediated DKD model in mice, urinary C-megalin excretion also increased via UEVs. Collectively, exocytosis-mediated urinary C-megalin excretion is linked with the megalin-mediated mechanism underlying the development and progression of DKD in T2DM.

Research Products

• [Journal Article] Exocytosis-Mediated Urinary Full-Length Megalin Excretion is Linked with the Pathogenesis of Diabetic Nephropathy (2017)
  • Author(s): De S, Kuwahara S, Hosojima M, Ishikawa T, Kaseda R, Sarkar P, Yoshioka Y, Kabasawa H, Iida T, Goto S, Toba K, Higuchi Y, Suzuki Y, Hara M, Kurosawa H, Narita I, Hirayama Y, Ochiya T, Saito A
  • Journal Title: Diabetes Volume: in press Issue: 5 Pages: 1391-1404
  • DOI: 10.2337/db16-1031
  • Peer Reviewed
• [Presentation] Mechanisms underlying urinary excretion of full-length and extracellular domain forms of megalin (2016)
  • Author(s): Shankhajit De，Shoji Kuwahara，Michihiro Hosojima，Tomomi Ishikawa，Ryohei Kaseda，Yusuke Yoshioka，Yoshiki Suzuki，Ichiei Narita，Takahiro Ochiya，Hiroyuki Kurosawa, Yoshiaki Hirayama, Akihiko Saito
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-06-17
• [Presentation] Mechanism of Increased Urinary Full-Length Megalin Excretion in Type 2 Diabetes Mellitus Patients with Nephropathy (2015)
  • Author(s): Shankhajit De, Shoji Kuwahara, Michihiro Hosojima, MD, PhD, Tomomi Ishikawa, MD, Ryohei Kaseda, MD, PhD, Yusuke Yoshioka, PhD, Yoshiki Suzuki, Ichiei Narita, MD, PhD, Takahiro Ochiya, PhD, Akihiko Saito, MD, PhD.
  • Organizer: American Society of Nephrology 48th Annual Meeting
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-11-03
  • Int'l Joint Research