Ephrin-B1 at the slit diaphragm controls podocyte function

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K19479
• 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: Fukusumi Yoshiyasu 新潟大学, 医歯学系, 准教授 (20609242)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: ポドサイト / 蛋白尿 / ネフローゼ症候群 / スリット膜 / Ephrin-B1 / Nephrin / JNK

Outline of Final Research Achievements

We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear. We show that podocyte-specific ephrin-B1 conditional knockout mice displayed alteration of the podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Analyses with the HEK cell expression system revealed that ephrin-B1 interacted with nephrin via the basal regions of extracellular domain. Nephrin-binding ephrin-B1 was phosphorylated by extracellular nephrin stimulation. The phosphorylation of ephrin-B1 was detected in rat glomeruli of the nephrotic model, induced by anti-nephrin antibody injection. Ephrin-B1 regulated the phosphorylation of JNK in glomeruli. Taken together, it is conceivable that ephrin-B1 in the podocyte is essential for maintaining the integrity of the glomerular filtration barrier and plays a critical role as a signal molecule controlling the podocyte functions.

Free Research Field

腎分子病態学

Academic Significance and Societal Importance of the Research Achievements

本研究で、スリット膜のバリア機能維持におけるEphrin-B1の役割を解明し、蛋白尿発症の新たな分子機構を明らかにした。また、ネフローゼ症候群の症例でEphrin-B1の発現が低下していることを発見した。Ephrin-B1の発現低下の抑制、リン酸化抑制、JNK活性を制御する薬剤、化合物が蛋白尿治療薬として有効である可能性を示した。