Journal
LABORATORY INVESTIGATION
Volume 96, Issue 1, Pages 49-59Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/labinvest.2015.133
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [22390259, 25461617]
- Grants-in-Aid for Scientific Research [15K09682, 15H04880, 22390259, 25461617] Funding Source: KAKEN
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In kidney glomeruli, mesangial cells provide structural support to counteract for expansile forces caused by pressure gradients and to regulate the blood flow. Glomerular injury results in proliferation and aberrant migration of mesangial cells, which is the pathological characteristic of mesangial proliferative glomerulonephritis. To date, molecular changes that occur in mesangial cells during glomerular injury and their association with the pathogenesis of glomerulonephritis remain largely unclear. During the search for proteins regulating the morphology of mesangial cells, we found that afadin, a multi-domain F-actin-binding protein, and beta-catenin are expressed in cell-cell contact sites of cultured mesangial cells and mesangial cells in vivo. Afadin forms a protein complex with beta-catenin in glomeruli and in cultured mesangial cells. Protein expression of afadin at mesangial intercellular junctions was dramatically decreased in mesangial proliferative nephritis in rats and in patients with glomerulonephritis. RNA interference-mediated depletion of afadin in cultured mesangial cells did not affect proliferation rate but resulted in delayed directional cell migration. Furthermore, reorientation of the Golgi complex at the leading edges of migrating cells in wound-healing assay was disturbed in afadindepleted cells, suggesting the role of aberrant migratory polarity in the pathogenesis of proliferative glomerulonephritis. These data shed light on glomerulonephritis-associated changes in cell-cell adhesion between mesangial cells, which might be related to migratory polarity.
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