FilGAP controls cell-extracellular matrix adhesion and process formation of kidney podocytes

• Published in: The FASEB journal Vol. 38; no. 5; p. e23504
• Main Authors: Saito, Koji, Yokawa, Seiji, Kurihara, Hidetake, Yaoita, Eishin, Mizuta, Sari, Tada, Kanae, Oda, Moemi, Hatakeyama, Hiroyasu, Ohta, Yasutaka
• Format: Journal Article
• Language: English
• Published: United States 15.03.2024
• Subjects: FilGAP; actin cytoskeleton; focal adhesion; PAK1; kidney podocyte; cell adhesion; rho small GTPase; Rac1; cell process
• ISSN: 1530-6860
• DOI: 10.1096/fj.202301691RR

The function of kidney podocytes is closely associated with actin cytoskeleton regulated by Rho small GTPases. Loss of actin-driven cell adhesions and processes is connected to podocyte dysfunction, proteinuria, and kidney diseases. FilGAP, a GTPase-activating protein for Rho small GTPase Rac1, is abundantly expressed in kidney podocytes, and its gene is linked to diseases in a family with focal segmental glomerulosclerosis. In this study, we have studied the role of FilGAP in podocytes in vitro. Depletion of FilGAP in cultured podocytes induced loss of actin stress fibers and increased Rac1 activity. Conversely, forced expression of FilGAP increased stress fiber formation whereas Rac1 activation significantly reduced its formation. FilGAP localizes at the focal adhesion (FA), an integrin-based protein complex closely associated with stress fibers, that mediates cell-extracellular matrix (ECM) adhesion, and FilGAP depletion decreased FA formation and impaired attachment to the ECM. Moreover, in unique podocyte cell cultures capable of inducing the formation of highly organized processes including major processes and foot process-like projections, FilGAP depletion or Rac1 activation decreased the formation of these processes. The reduction of FAs and process formations in FilGAP-depleted podocyte cells was rescued by inhibition of Rac1 or P21-activated kinase 1 (PAK1), a downstream effector of Rac1, and PAK1 activation inhibited their formations. Thus, FilGAP contributes to both cell-ECM adhesion and process formation of podocytes by suppressing Rac1/PAK1 signaling.