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A group led by the Department of Cell Biology at the Kidney Research Center, Niigata University, has identified a novel Ca²⁺-independent pathogenic mechanism of nephrotic syndrome. The study is published in The American Journal of Pathology.

The glomerulus is the filtration unit of the kidney, and the glomerular capillary wall functions as a barrier that prevents plasma proteins from leaking into the urine. Proteinuria, a clinical manifestation of impaired glomerular filtration barrier function, is an aggravating factor that can contribute to kidney failure. Furthermore, proteinuria has been reported to be a risk factor for cardiovascular and cerebrovascular diseases.

Glomerular epithelial cells (podocytes) are located at the outer layer of the glomerular capillary wall and possess unique cellular extensions called foot processes. Adjacent foot processes are connected by slit diaphragms, which are thought to function as the final barrier against proteinuria.

Although a subset of nephrotic syndrome cases has been reported to be caused by autoantibodies against nephrin, a component of the slit diaphragm, the etiology of nephrotic syndrome remains poorly understood.

The group focused on Ephrin-B1, a nephrin-binding protein, and demonstrated that direct stimulation of Ephrin-B1 with soluble EphB2 or an anti-Ephrin-B1 antibody induces podocyte injury. The study showed that Ephrin-B1 stimulation induces the phosphorylation of both Ephrin-B1 and nephrin, leading to podocyte injury independently of Ca²⁺ influx. In contrast, TRPC6-mediated Ca²⁺ influx is required for podocyte injury induced by anti-nephrin antibodies.

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