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J Am Soc Nephrol. 2017 Dec;28(12):3545-3562. doi: 10.1681/ASN.2016091021. Epub 2017 Aug 3.

Kindlin-2 Association with Rho GDP-Dissociation Inhibitor α Suppresses Rac1 Activation and Podocyte Injury.

Sun Y1,2, Guo C3, Ma P3, Lai Y4, Yang F3, Cai J3, Cheng Z3, Zhang K3, Liu Z3, Tian Y3, Sheng Y3, Tian R2,5, Deng Y3,2, Xiao G1,2,4, Wu C1,2,6.

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Departments of Biology and
Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
Departments of Biology and.
Department of Orthopedic Surgery, Rush University Medical Center, Chicago, Illinois; and.
Chemistry, and.
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.


Alteration of podocyte behavior is critically involved in the development and progression of many forms of human glomerular diseases. The molecular mechanisms that control podocyte behavior, however, are not well understood. Here, we investigated the role of Kindlin-2, a component of cell-matrix adhesions, in podocyte behavior in vivo Ablation of Kindlin-2 in podocytes resulted in alteration of actin cytoskeletal organization, reduction of the levels of slit diaphragm proteins, effacement of podocyte foot processes, and ultimately massive proteinuria and death due to kidney failure. Through proteomic analyses and in vitro coimmunoprecipitation experiments, we identified Rho GDP-dissociation inhibitor α (RhoGDIα) as a Kindlin-2-associated protein. Loss of Kindlin-2 in podocytes significantly reduced the expression of RhoGDIα and resulted in the dissociation of Rac1 from RhoGDIα, leading to Rac1 hyperactivation and increased motility of podocytes. Inhibition of Rac1 activation effectively suppressed podocyte motility and alleviated the podocyte defects and proteinuria induced by the loss of Kindlin-2 in vivo Our results identify a novel Kindlin-2-RhoGDIα-Rac1 signaling axis that is critical for regulation of podocyte structure and function in vivo and provide evidence that it may serve as a useful target for therapeutic control of podocyte injury and associated glomerular diseases.


Kindlin-2; Rac1; RhoGDIα; Slit diaphragms; podocyte

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