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1 Department of Pediatrics, University of Wisconsin Medical School, Madison, WI, USA
2 Department of Opthalmology and Visual Sciences, University of Wisconsin Medical School, Madision, WI, USA
* To whom correspondence should be addressed. E-mail: cmsorenson{at}wisc.edu.
Bcl-2 protects cells from apoptosis initiated by a variety of stimuli including loss of cell adhesion. Bcl-2 -/- mice develop renal hypoplastic/cystic dysplasia with renal cyst formation coinciding with renal maturation in normal mice. To gain a better understanding of the role cell adhesive mechanisms play during renal maturation we generated proximal tubule and collecting duct cell lines from postnatal day 10 (P10) and P20 bcl-2 +/+ and bcl-2 -/- mice. Very little is known about the role cell adhesive and migratory mechanisms play during renal maturation. We observed that modulation of cell adhesive properties, which normally occur in a nephron segment specific manner during renal maturation, and cell migration were altered in cells from bcl-2 -/- mice. Enhanced migration of bcl-2 -/- proximal tubule cells in a scratch wound assay was completely inhibited by incubation with PP1 (Src inhibitor) and moderately affected by incubation with SB203580 (p38 inhibitor). These cells expressed increased levels of fibronectin and had numerous central focal adhesions. P20 bcl-2 -/- proximal tubule cells adhered to fibronectin, but adhered poorly to collagen, vitronectin or laminin. Collecting duct cells, similar to proximal tubule cells from bcl-2 -/- mice, demonstrated enhanced migration in a scratch wound assay which was inhibited by incubation with PP1. Migration of these cells was moderately affected by incubation with PD98059 (MEK inhibitor) or LY294002 (PI 3 kinase inhibitor) while incubation with SB203580 had no effect. P10 bcl-2 -/- collecting duct cells also expressed increased levels of fibronectin but decreased levels of thrombospondin-1 and demonstrated precocious binding to fibronectin and vitronectin compared to bcl-2 +/+ cells. The ability of P20 bcl-2 +/+ collecting duct cells to adhere to fibronectin and vitronectin corresponded with a decline in thrombospondin-1 expression. Therefore, alterations in cell adhesive and migratory characteristics may be an early indicator of aberrant renal epithelial cell differentiation.
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