Podocyte RhoGTPases: new therapeutic targets for nephrotic syndrome?

Abstract

Podocytes, or glomerular epithelial cells, form the final layer in the glomerular capillary wall of the kidney. Along with the glomerular basement membrane and glomerular endothelial cells, they make up the glomerular filtration barrier which allows the passage of water and small molecules and, in healthy individuals, prevents the passage of albumin and other key proteins. The podocyte is a specialised and terminally differentiated cell with a specific cell morphology that is largely dependent on a highly dynamic underlying cytoskeletal network and that is essential for maintaining glomerular function and integrity in healthy kidneys. The RhoGTPases (RhoA, Rac1 and Cdc42), which act as molecular switches that regulate actin dynamics, are known to play a crucial role in maintaining the cytoskeletal and molecular integrity of the podocyte foot processes in a dynamic manner. Recently, novel protein interaction networks that regulate the RhoGTPases in the podocyte and that are altered by disease have been discovered. This review will discuss these networks and their potential as novel therapeutic targets in nephrotic syndrome. It will also discuss the evidence that they are direct targets for (a) steroids, the first-line agents for the treatment of nephrotic syndrome, and (b) certain kinase inhibitors used in cancer treatment, leading to nephrotoxicity.

MRTF: Basic Biology and Role in Kidney Disease

“…RhoA has been documented to play a role in a wide range of kidney pathologies, and in principle dysregulation of MRTF may play a role in each of these because dysregulated RhoA signaling can disrupt gene expression primarily via MRTF. Important examples include congenital and acquired proteinuric glomerular diseases, podocyte and mesangial cell injuries [ 8 , 9 , 267 ]. Further, any pathology associated with altered cytoskeleton organization is a potential “myrtfopathy”, impacting MRTF-dependent transcription.…”

“…The cytoskeleton is also the structural basis of cell motility. It is thus not surprising that alterations in the activities of Rho family proteins, either due to genetic defects or provoked by cellular injuries, are associated with, and play significant pathogenic roles in acute and chronic kidney diseases [ 6 , 7 , 8 , 9 ]. However, the cytoskeleton affects organ function not only through its structural roles; the cytoskeleton is a regulator of gene expression as well.…”

The effectiveness of cyclosporine A for patients with steroid-resistant nephrotic syndrome

“…The precise effect of this circulating factor on podocyte biology also needs to be clarified. [ 15 ] We suspect that the circulating factor is in some way related to the immune system, since all currently effective treatments are with immunosuppressive medications. The purpose of this study is to determine the efficacy and safety of CsA for patients with SRNS.…”

Rho GTPase regulatory proteins in podocytes

“…For more extensive overviews of the roles of Rho GTPases in podocytes, readers are referred to additional reviews. [17][18][19] Rho GTPases act as molecular switches by existing in either inactive GDP-bound or active GTP-bound conformation. This GDP/GTP cycle is primarily regulated by the three families of J o u r n a l P r e -p r o o f proteins; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and GDP dissociation inhibitors (GDIs).…”