Niigata, Japan – A group led by the Department of Cell Biology at the Kidney Research Center, Niigata University identified a novel Ca2+-independent pathogenic mechanism of nephrotic syndrome.
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.
A group at Niigata University 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. The researchers further elucidated the signaling cascades downstream of Ephrin-B1 and nephrin phosphorylation. Phosphorylated Ephrin-B1 dissociates from nephrin and Par6, another Ephrin-B1-binding protein. Par6, once released from Ephrin-B1, subsequently interacts with the signaling protein Cdc42 and enhances its activity. Increased Cdc42 activity promotes calcineurin (CaN) activity, which in turn alters the regulation of the transcription factor Snail, resulting in reduced mRNA expression of nephrin and Ephrin-B1. Increased Cdc42 activity activates Stat3 independently of CaN. Activated Stat3 induces the expression of claudin-1, a marker of podocyte dedifferentiation. The study demonstrated that a Cdc42 inhibitor prevented both the downregulation of nephrin and Ephrin-B1 expression and the induction of claudin-1 expression. In contrast, a calcineurin inhibitor and an angiotensin II type 1 receptor blocker (ARB) prevented the downregulation of nephrin and Ephrin-B1 expression but failed to prevent claudin-1 induction. The 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.
