Role of actin cytoskeleton in podocytes

Abstract

The selectivity of the glomerular filter is established by physical, chemical, and signaling interplay among its three core constituents: glomerular endothelial cells, the glomerular basement membrane, and podocytes. Functional impairment or injury of any of these three components can lead to proteinuria. Podocytes are injured in many forms of human and experimental glomerular disease, including minimal change disease, focal segmental glomerulosclerosis, and diabetes mellitus. One of the earliest signs of podocyte injury is loss of their distinct structure, which is driven by dysregulated dynamics of the actin cytoskeleton. The status of the actin cytoskeleton in podocytes depends on a set of actin binding proteins, nucleators and inhibitors of actin polymerization, and regulatory GTPases. Mutations that alter protein function in each category have been implicated in glomerular diseases in humans and animal models. In addition, a growing body of studies suggest that pharmacological modifications of the actin cytoskeleton have the potential to become novel therapeutics for podocyte-dependent chronic kidney diseases. This review presents an overview of the essential proteins that establish actin cytoskeleton in podocytes and studies demonstrating the feasibility of drugging actin cytoskeleton in kidney diseases.

Trial registration: ClinicalTrials.gov NCT04079803 NCT03199586.

Keywords: Actin binding proteins (ABPs); Actin cytoskeleton; Glomerular diseases; Nucleators of actin polymerization; Podocytes; Regulatory GTPases.

Conflict of interest statement

Conflict of interest:

S. S. is co-founders and shareholder of Trisaq, a biotechnology company that develops novel kidney-protective therapies.

© 2020. IPNA.

Figures

Figure 1.. Schematics of the glomerular filter.

Specificity of the kidney filter is maintained by fenestrated endothelium, the glomerular basement membrane (GBM) and glomerular podocytes. The structure of podocyte foot processes (FPs) is regulated by two signaling platforms: focal adhesions (FAs) and the slit-diaphragm (SD). Those two hubs integrate ‘inside out’ and ‘outside in’ signaling, which defines the global organization of the actin cytoskeleton. The status of the actin cytoskeleton is defined by regulatory GTPases, actin binding proteins (ABPs) and actin nucleation factors. Two major actin structures are tight actin bundles and loose networks, both of which are established by actin crosslinking proteins.

Figure 2.. The GTPase cycle of regulatory GTPases.

When in the GTP-bound state, these enzymes interact with cell-type specific downstream effectors, thus activating actin nucleators and actin crosslinking proteins. GTP hydrolysis requires the binding of GTPase activating proteins (GAPs), and a subsequent switch into the GDP-bound conformation disengages interactions between GTPase and upstream effectors. Interactions with GDP exchange factors (GEF) promotes re-activation of the GTPase. Examples of the regulatory proteins are indicated in the figure. GTPase cycle of large GTPase Dynamin (Dyn) is regulated by its oligomerization status, with dimers and tetramers being inactive form of the enzyme and rings being the active form of the enzyme.