HMN 2025: How Elevated cdc42 activity is a key initiation event leading to proteinuria, research reveals

A group led by the Department of Cell Biology at the Kidney Research Center, Niigata University revealed that elevated activity of cdc42 is a critical initiation event leading to proteinuria, and proposed that suppression of cdc42 activity could be a promising therapy for nephrotic syndrome. Their paper is published in the Journal of the American Society of Nephrology.

Glomerulus is a filtration unit of the kidney, and the glomerular capillary wall functions as a barrier, preventing the leak of plasma protein into urine.

Proteinuria is a clinical symptom showing dysfunction of the barrier of the glomerular capillary wall, and is an aggravating factor leading to kidney failure. Proteinuria is reported to be a risk factor for cardiovascular and cerebrovascular diseases.

Glomerular epithelial cells (podocyte) are located in the outer layer of the glomerular capillary wall, and possess unique processes called foot processes. Neighboring foot processes are bridged by the slit diaphragm.

It is accepted that the slit diaphragm functions as a final barrier preventing proteinuria. Recent clinical studies have reported that the major parts of nephrotic syndrome are caused by autoantibody against nephrin, a key component of the slit diaphragm.

A group at Niigata University analyzed signaling pathways in podocyte after stimulation by an anti-nephrin antibody. The study revealed that ephrin-B1 in the slit diaphragm interacted with nephrin and Par6, and that the anti-nephrin antibody caused the phosphorylations of nephrin and ephrin-B1 in a Ca²⁺ influx–dependent manner.

Phosphorylated ephrin-B1 was dissociated from nephrin and also from Par6, and Par6 came to interact with cdc42.

The binding of Par6 promoted cdc42 activity. Elevated cdc42 activity promoted calcineurin activity, activated Snail, a transcription factor, and decreased mRNA expression of nephrin, ephrin-B1 and other functional molecules of slit diaphragm.

The altered expression of the functional molecules induced the loss of barrier function of the slit diaphragm, which leads to proteinuria. The study also showed that a cdc42 inhibitor restored the expression of slit diaphragm functional molecules.

Researchers argue that the regulation of cdc42 activity could be a promising therapy for nephrotic syndrome.