Authors
Yoshiyasu Fukusumi, Ying Zhang, Hidenori Yasuda, Mutsumi Kayaba, Hiroshi Kawachi
Published in
The American journal of pathology. Oct 13, 2026. Epub Oct 13, 2026.
Abstract
Although a subset of nephrotic syndrome has been reported to be caused by autoantibodies against nephrin, its etiology remains poorly understood. A previous study demonstrated that anti-nephrin antibodies phosphorylate not only nephrin but also Ephrin-B1 at the slit diaphragm of podocytes. However, the pathogenic role of Ephrin-B1 in nephrotic syndrome remains unclear. The present study, using cultured human podocytes, demonstrated that direct stimulation of Ephrin-B1 with soluble EphB2 or an anti-Ephrin-B1 antibody induced phosphorylation of both Ephrin-B1 and nephrin. Neither EphB2 nor the anti-Ephrin-B1 antibody induced calcium influx, whereas the anti-nephrin antibody did. Phosphorylated Ephrin-B1 dissociated from Par6, and the released Par6 subsequently interacted with Cdc42. This interaction promoted Cdc42 activation, leading to altered regulation of Snail and STAT3. These alterations resulted in decreased expression of nephrin and Ephrin-B1 and induced claudin-1 expression. A Cdc42 inhibitor prevented both the downregulation of nephrin and Ephrin-B1 and the induction of claudin-1 expression. In contrast, a calcineurin inhibitor and an angiotensin II type 1 receptor blocker prevented the downregulation of nephrin and Ephrin-B1 but failed to prevent claudin-1 induction. This study proposed a novel potential etiology of nephrotic syndrome caused by direct stimulation of Ephrin-B1. Targeting Cdc42 may represent a more effective therapeutic strategy for restoring podocyte homeostasis.
PMID:
42869287
Bibliographic data and abstract were imported from PubMed on 14 Oct 2026.
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