A critical role of the podocyte cytoskeleton in the pathogenesis of glomerular proteinuria and autoimmune podocytopathies

Abstract

Selective glomerular filtration relies on the membrane separating the glomerular arterioles from the Bowman space. As a major component of the glomerular filtration barrier, podocytes form foot processes by the actin cytoskeleton, which dynamically adjusts in response to environmental changes to maintain filtration barrier integrity. The slit diaphragms bridge the filtration slits between neighboring foot processes and act as signaling hubs interacting with the actin cytoskeleton. Focal adhesions relay signals to regulate actin dynamics while allowing podocyte adherence to the basement membrane. Mutations in actin regulatory and signaling proteins may disrupt the actin cytoskeleton, resulting in foot process retraction, effacement, and proteinuria. Large‐scale gene expression profiling platforms, transgenic animal models, and other in vivo gene delivery methods now enhance our understanding of the interactions among podocyte focal adhesions, slit diaphragms, and actin dynamics. In addition, our team found that at least 66% of idiopathic nephrotic syndrome (INS) children have podocyte autoantibodies, which was defined as a new disease subgroup‐, autoimmune podocytopathies. This review outlines the pathophysiological mechanisms of podocyte cytoskeleton protein interactions in proteinuria and glomerular podocytopathy.

Network pharmacology and molecular docking of endogenous active metabolites in diabetic kidney disease

“…The protein network governing podocyte foot process development mirrors that of synaptic development in neurons [ 17–19 ]. Genetic studies highlight the significance of actin-regulatory proteins and upstream signaling factors for the integrity of podocyte foot processes, emphasizing actin’s central role [ 20 ]. Dynein’s function in podocytes may be mediated by its role in the actin cytoskeleton [ 21 , 22 ].…”

Cytoskeleton Rearrangement in Podocytopathies: An Update

“…The actin cytoskeleton is the core component of podocytes and is mainly abundant in the FPs. It plays a dominant role in establishing and maintaining the distinct architecture of podocytes [ 7 ]. The composition of the actin cytoskeleton in the FPs contains two groups: central actin bundles above the SD and a network of cortical actin fibers beneath the curved plasma membrane of the FPs [ 18 ].…”

“…The actin cytoskeleton is strongly sensitive and responsive to the mechanical stress that podocytes face [ 20 ]. The AFs provide a structural and functional basis, thus building the cytoarchitecture of podocytes and enhancing adhesion to the extracellular matrix [ 7 , 16 ]. The central actin bundles are engaged in generating tensile forces, whereas the cortical actin network is necessary to uphold the elaborate morphology of FPs [ 15 ].…”

“…Actin cytoskeleton dysfunction is the principal mechanism of FPE in podocytes [ 7 ]. Podocytes are extremely motile, particularly after injury, and the morphology of podocytes is highly dependent on the actin cytoskeleton, which is regulated by cytoskeleton-associated proteins [ 8 ].…”

Comprehensive mapping of B lymphocyte immune dysfunction in idiopathic nephrotic syndrome children

“…These podocyte autoantibodies are positively correlated with proteinuria, and their titer decreases rapidly after effective treatment. 3 , 4 Considering that B lymphocytes exert an immune response in INS patients, we performed CyTOF analyses including 11 peripheral blood mononuclear cell samples from INS children by a prospectively designated cohort to profile specific immune signatures of B lymphocytes in INS patients (Table S1 ). The two predefined marker panels (Panels A and B) were designed to characterize the composition and function of B lymphocytes (Tables S2 and S3 ).…”