Direct stimulation of the protein Ephrin-B1 triggers podocyte injury in the kidneys, independent of calcium influx, according to research published in 2026 by Niigata University.
This discovery identifies a previously unknown mechanism behind nephrotic syndrome, a condition characterized by the kidneys leaking excessive protein into the urine.
The study, conducted by the Department of Cell Biology at the Kidney Research Center, maps how the glomerular filtration barrier—the body’s primary kidney filter—is compromised. When these barriers fail, patients develop proteinuria. This clinical manifestation acts as an aggravating factor that contributes to kidney failure and is recognized as a risk factor for cerebrovascular and cardiovascular diseases.
While previous research identified autoantibodies against nephrin as a cause for some cases of nephrotic syndrome, the underlying etiology has remained largely unclear.
The Niigata University team focused on the interaction between nephrin and Ephrin-B1, demonstrating that direct stimulation of Ephrin-B1 via soluble EphB2 or an anti-Ephrin-B1 antibody triggers podocyte damage. This pathway operates distinctly from other known mechanisms, such as TRPC6-mediated Ca²⁺ influx, which is required for injury caused by anti-nephrin antibodies.
The team successfully mapped the signaling cascades following Ephrin-B1 and nephrin phosphorylation. During this process, phosphorylated Ephrin-B1 dissociates from nephrin and Par6. This elevated Cdc42 activity promotes calcineurin (CaN) function, which alters the regulation of the Snail transcription factor, ultimately reducing mRNA expression of Ephrin-B1 and nephrin.
The researchers evaluated potential therapeutic interventions and proposed that targeting Cdc42 may represent a more effective strategy for restoring podocyte homeostasis, according to Fukusumi, et al.
Earlier coverage: Researchers at Niigata University Identify Calcium-Independent Mechanism in Nephrotic Syndrome