Abstract
The first step of urine formation is the selective filtration of the plasma into the urinary space at the kidney structure called the glomerulus. The filtration barrier of the glomerulus allows blood cells and large proteins such as albumin to be retained while eliminating the waste products of the body. The filtration barrier consists of three layers: fenestrated endothelial cells, glomerular basement membrane, and podocytes. Podocytes are specialized epithelial cells featured by numerous, actin-based projections called foot processes. Proteins on the foot process membrane are connected to the well-organized intracellular actin network. The Rho family of small GTPases (Rho GTPases) act as intracellular molecular switches. They tightly regulate actin dynamics and subsequent diverse cellular functions such as adhesion, migration, and spreading. Previous studies using podocyte-specific transgenic or knockout animal models have established that Rho GTPases are crucial for the podocyte health and barrier function. However, little attention has been paid regarding subcellular locations where distinct Rho GTPases contribute to specific functions. In the current review, we discuss cellular events involving the prototypical Rho GTPases (RhoA, Rac1, and Cdc42) in podocytes, with particular focus on the subcellular compartments where the signaling events occur. We also provide our synthesized views of the current understanding and propose future research directions.
Highlights
The kidney glomerulus is a structure with entangled capillaries where the first step of urine formation occurs by filtering the plasma into the urinary space
The results suggest that KANK suppresses Rho GTPase, predominantly RhoA, activity via RhoGDIa, but additional experiments are needed to validate that the signal is dependent on RhoA
It is evident that Rho GTPases interact with multiple proteins in podocytes and transduce signals from the cell membrane to the sub-membranous actin cytoskeleton or in the cytoplasm and the nucleus
Summary
The kidney glomerulus is a structure with entangled capillaries where the first step of urine formation occurs by filtering the plasma into the urinary space. Many of the foot process membrane proteins are connected to the well-organized intracellular actin network. This network undergoes substantial changes in proteinuric kidney disease, leading to profound morphological changes known as “foot process effacement” [2,3,5,6]. Several reviews are available, including ours, that provide the overview of the role of Rho GTPases in podocytes [15,16,17] These reviews discuss the known roles of Rho GTPases and their regulatory proteins based on in vitro/in vivo studies and disease-causing variants in humans. We discuss cellular events involving Rho GTPases in podocytes, with particular focus on the subcellular compartment where the signaling events occur. MiR-25 is included, it is not a protein, as discussed in the text
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