Dissociation of NEPH1 from nephrin is involved in development of a rat model of focal segmental glomerulosclerosis.

Abstract	Focal segmental glomerulosclerosis (FSGS) is a disease showing severe proteinuria, and the disease progresses to end-stage kidney failure in many cases. However, the pathogenic mechanism of FSGS is not well understood. The slit diaphragm (SD), which bridges the neighboring foot processes of glomerular epithelial cells, is understood to function as a barrier of the glomerular capillary wall. To investigate the role of SD dysfunction in the development of FSGS, we analyzed the expression of SD-associated molecules in rat adriamycin-induced nephropathy, a mimic of FSGS. The staining of the SD molecules nephrin, podocin, and NEPH1 had already shifted to a discontinuous dotlike pattern at the initiation phase of the disease, when neither proteinuria nor any morphological alterations were detected yet. The alteration of NEPH1 expression was the most evident among the molecules examined, and NEPH1 was dissociated from nephrin at the initiation phase. On day 28, when severe proteinuria was detected and sclerotic changes were already observed, alteration of the expressions of nephrin, podocin, and NEPH1 worsened, but no alteration in the expression of other SD-associated molecules or other podocyte molecules was detected. It is postulated that the dissociation of NEPH1 from nephrin initiates proteinuria and that the SD alteration restricted in these molecules plays a critical role in the development of sclerotic changes in FSGS.
Authors	Yasuhiro Otaki, Naoko Miyauchi, Mutsumi Higa, Akira Takada, Takeshi Kuroda, Fumitake Gejyo, Fujio Shimizu, Hiroshi Kawachi
Journal	American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 295 Issue 5 Pg. F1376-87 (Nov 2008) ISSN: 1931-857X [Print] United States
PMID	18715943 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Antibodies CD2-associated protein Cytoskeletal Proteins Integrins Intracellular Signaling Peptides and Proteins Kirrel1 protein, rat Membrane Proteins NPHS2 protein Phosphoproteins Sialoglycoproteins Tjp1 protein, rat Zonula Occludens-1 Protein nephrin podocalyxin Doxorubicin
Topics	Adaptor Proteins, Signal Transducing (genetics, metabolism) Animals Antibodies (immunology) Blotting, Western Cloning, Molecular Cytoskeletal Proteins (genetics, metabolism) Doxorubicin Embryo, Mammalian (metabolism) Female Gene Expression Regulation, Developmental Glomerulosclerosis, Focal Segmental (chemically induced, immunology, metabolism) Integrins (genetics, metabolism) Intracellular Signaling Peptides and Proteins (genetics, metabolism) Kidney Glomerulus (embryology, metabolism, pathology) Kidney Tubules (metabolism, pathology) Membrane Proteins (genetics, immunology, metabolism) Molecular Sequence Data Phosphoproteins (genetics, metabolism) Podocytes (metabolism) Protein Binding Proteinuria (urine) Rats Rats, Wistar Reverse Transcriptase Polymerase Chain Reaction Sialoglycoproteins (genetics, metabolism) Zonula Occludens-1 Protein

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