Research Identifies Elevated cdc42 Activity as a Trigger for Proteinuria and Potential Therapeutic Target

Recent research conducted by the Department of Cell Biology at Niigata University has uncovered that increased activity of the protein cdc42 plays a crucial role in the initial development of proteinuria, a hallmark of various kidney disorders. The study highlights that the activation of cdc42 in podocytes, specialized cells lining the glomerular capillary wall, triggers a cascade of molecular events leading to the breakdown of the kidney's filtration barrier. This process is mediated by the interaction and phosphorylation changes of ephrin-B1 and nephrin, key components of the slit diaphragm, which normally prevent plasma proteins from leaking into urine. When stimulated by an anti-nephrin antibody, ephrin-B1 dissociates from nephrin and Par6, which in turn leads to an increase in cdc42 activity. Elevated cdc42 promotes calcineurin activity and activates the transcription factor Snail, resulting in decreased expression of critical slit diaphragm molecules such as nephrin and ephrin-B1. This impairment compromises the glomerular filtration barrier, causing proteinuria. Significantly, the study found that inhibiting cdc42 can restore the expression of these vital molecules, suggesting that targeting cdc42 activity could be an effective strategy for treating nephrotic syndrome and preventing progression to kidney failure. The findings underscore the potential of cdc42 inhibitors in therapeutic applications and advance our understanding of the molecular mechanisms underlying glomerular barrier dysfunction. The full study is published in the Journal of the American Society of Nephrology. Source: Niigata University

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