Wnt7b Signaling from the Ureteric Bud Epithelium Regulates Medullary Capillary Development

摘要

The renal vasculature is integral to the physiologic function of the kidneys in regulating hemodynamics of the body and maintaining organ health. The close inter-relationship of capillaries and the renal epithelium is key to renal physiology, but how renal tubules regulate capillary development remains unclear. Our previous work showed that Wnt7b is expressed in the ureteric trunk epithelium and activates canonical Wnt signaling in the surrounding medullary interstitium, where the capillaries reside. In this study, we showed by immunofluorescence that the target interstitial cells of Wnt7b/canonical Wnt signaling are mural cells of periureteric bud capillaries in the nascent renal medulla of embryonic mice. Genetic ablation of Wnt7b enhanced the proliferation of Wnt7b target mural cells, an effect that associated with decreased expression of PDGFR beta and p57kip2, a cyclin-dependent kinase inhibitor, in these cells. Furthermore, Wnt7b regulated lumen formation of the capillary endothelium in the renal medulla. In the absence of Wnt7b signaling, the periureteric bud medullary capillaries displayed narrower lumens lined with less flattened endothelial cells and a significantly increased presence of luminal endothelial cell-cell junctions, a transient configuration in the forming blood vessels in the controls. Moreover, the absence of Wnt7b led to greatly diminished levels of vascular endothelial (VE)-cadherin at the cell surface in these blood vessels. VE-cadherin is essential for blood vessel lumen formation; thus, Wnt7b may regulate lumen formation through modulation of VE-cadherin localization. Overall, these results indicate a novel role of Wnt7b signaling and the ureteric bud epithelium in renal medullary capillary development.