Abstract
Nephrotic syndrome is a kidney disease featured by heavy proteinuria. It is caused by injury to the specialized epithelial cells called “podocytes” within the filtration unit of the kidney, glomerulus. Previous studies showed that hyperactivation of the RhoGTPase, Rac1, in podocytes causes podocyte injury and glomerulosclerosis (accumulation of extracellular matrix in the glomerulus). However, the mechanism by which Rac1 is activated during podocyte injury is unknown. Trio is a guanine nucleotide exchange factor (GEF) known to activate Rac1. By RNA-sequencing, we found that Trio mRNA is abundantly expressed in cultured human podocytes. Trio mRNA was also significantly upregulated in humans with minimal change disease and focal segmental glomerulosclerosis, two representative causes of nephrotic syndrome. Reduced expression of Trio in cultured human podocytes decreased basal Rac1 activity, cell size, attachment to laminin, and motility. Furthermore, while the pro-fibrotic cytokine, transforming growth factor β1 increased Rac1 activity in control cells, it decreases Rac1 activity in cells with reduced Trio expression. This was likely due to simultaneous activation of the Rac1-GTPase activation protein, CdGAP. Thus, Trio is important in the basal functions of podocytes and may also contribute to glomerular pathology, such as sclerosis, via Rac1 activation.
Highlights
Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and edema
Together with glomerular endothelial cells and the glomerular basement membrane (GBM), podocytes play a critical role in maintaining barrier function of the glomerulus; podocyte injury causes foot processes to retract into the cell body, leading to proteinuria
RhoGTPases act as a molecular switch, alternating between the active, GTP-bound form, and the inactive, GDP-bound form. They are regulated by three groups of proteins—guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs)
Summary
Nephrotic syndrome is characterized by proteinuria (leakage of protein from the blood into the urine), hypoalbuminemia (decreased levels of albumin the blood), and edema. RhoGTPases act as a molecular switch, alternating between the active, GTP-bound form, and the inactive, GDP-bound form They are regulated by three groups of proteins—guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). Another study investigated the role of two closely related GEFs, Dock and Dock, in podocytes They were expressed in podocytes in vivo, their knockout in the podocyte neither resulted in kidney abnormalities nor protected mice from lipopolysaccharide (LPS)-induced foot process effacement and proteinuria [13]. This suggests that Dock and Dock do not play an important role in activating Rac in podocytes. The current study is aimed at defining the role of Trio in the podocyte’s functions
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