{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNPHS1 encodes nephrin, a transmembrane adhesion protein that is essential for establishing the specialized slit diaphragm between podocyte foot processes in the kidney. Nephrin’s extracellular immunoglobulin‐like domains mediate homophilic interactions that not only enable cell–cell adhesion but also help form a dynamic filtration barrier, as revealed by high‐resolution studies of the slit diaphragm architecture. In addition, NPHS1 transcription is tightly regulated—its promoter is activated by key factors such as WT1—and its expression is observed not only in podocytes but also in other vascular cells, underscoring a broader role in maintaining vascular barrier properties."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its structural function, nephrin actively transduces extracellular signals to orchestrate intracellular cytoskeletal dynamics. Nephrin undergoes tyrosine phosphorylation upon clustering at the podocyte membrane, a modification that creates binding sites for adaptor proteins such as Nck and other effectors. These interactions promote local actin polymerization and are critical for sustaining foot process morphology and dynamic responses—such as calcium flux mediated by PLC‐γ1 recruitment—thereby integrating external stimuli (e.g., via VEGF or insulin) with cytoskeletal rearrangement."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations or altered regulation of NPHS1 disrupt nephrin’s dual structural and signaling roles, leading to impaired slit diaphragm integrity and proteinuria. Indeed, NPHS1 genetic defects are a principal cause of congenital and early‐onset nephrotic syndromes—including the classic Finnish type—and contribute to a spectrum of glomerular diseases, such as focal segmental glomerulosclerosis and diabetic nephropathy. In some instances, aberrant posttranscriptional regulation (for example via PPARα‐mediated stabilization) or misdirected endocytosis (through altered planar cell polarity signals) may further perturb nephrin expression and localization. This clinical variability highlights the importance of NPHS1 both as a key regulator of podocyte function and as a potential biomarker or therapeutic target in proteinuric kidney diseases, with emerging genetic markers even informing responses to antihypertensive therapy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ania Koziell, Victor Grech, Sagair Hussain, et al. 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