Clarification of the regulatory mechanism of Rac1 in podocytes

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16164
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53040:Nephrology-related
• Research Institution: Osaka University
• Principal Investigator: Matsuda Jun 大阪大学, 大学院医学系研究科, 特任助教(常勤) (10778260)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 糸球体上皮細胞 / Rho GTPase

Outline of Final Research Achievements

Rho GTPases, including Rac1, play important roles in actin cytoskeletal remodeling required for cell morphology. While previous studies have shown that Rac1 activation in podocytes causes foot process effacement and proteinuria, the regulatory mechanism of Rac1 remains unknown. In the current study, using proximity-dependent biotin identification, we identified that Rac1 in immortalized human podocytes (HP) interacts with GIT ArfGAP 2 (GIT2). GIT2 localized with paxillin in focal adhesions. GTP-bound (active) Rac1 levels were higher in GIT2 knockdown (KD) HP than in controls. GIT2 KD elicited cell spreading with marked lamellipodial protrusions, which was significantly attenuated by the Rac1 inhibitor. Our findings demonstrate that GIT2 localizes in the focal adhesion in podocytes and plays a critical role in podocyte cytoskeletal dynamics. Rac1 regulation by GIT2 may offer a new therapeutic target.

Free Research Field

ポドサイト

Academic Significance and Societal Importance of the Research Achievements

本研究ではポドサイトのRac1活性を制御する蛋白としてGIT2を同定した。GIT2は接着斑に局在し、Rac1の活性を抑制することでポドサイト形態の維持を行っていると考えられる。Rac1の亢進は、足突起の形態変化・機能異常以外に、アルドステロン非依存性にミネラルコルチコイド受容体を活性化することが知られており、それも腎障害を引き起こす機序の1つと考えられている。現在いくつかのミネラルコルチコイド受容体阻害薬が腎疾患の治療に用いられているが、GIT2がそれに代わる新規治療標的となる可能性がある。