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Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway
- Source :
- Journal of the American Society of Nephrology. 29:1462-1474
- Publication Year :
- 2018
- Publisher :
- Ovid Technologies (Wolters Kluwer Health), 2018.
-
Abstract
- Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear. Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti-nephrin antibody-induced nephropathy. Results Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing a mutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1–promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody-induced nephropathy. Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury.
- Subjects :
- 0301 basic medicine
animal structures
030232 urology & nephrology
Ephrin-B1
urologic and male genital diseases
Antibodies
Podocyte
Nephrin
Mice
03 medical and health sciences
0302 clinical medicine
Cell Movement
Conditional gene knockout
medicine
Animals
Humans
Phosphorylation
Mice, Knockout
biology
urogenital system
Podocytes
Chemistry
Kinase
JNK Mitogen-Activated Protein Kinases
Membrane Proteins
General Medicine
Rats
Cell biology
HEK293 Cells
Basic Research
030104 developmental biology
medicine.anatomical_structure
nervous system
Nephrology
embryonic structures
Knockout mouse
Slit diaphragm
biology.protein
Nephrosis
sense organs
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 15333450 and 10466673
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Journal of the American Society of Nephrology
- Accession number :
- edsair.doi.dedup.....26c1fa952662c9b1fedd4f8cb107b543