Host Lymphotoxin-beta Receptor Signaling Is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites

摘要

The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-beta receptor (LT beta R) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LT beta R antagonist treatment or in the omenta of Ltbr knockout (Ltbr(-/-)) mice, the host LT beta R signals were found to be crucial for obtaining a well-vascularized kidney graft. Indeed, defective LT beta R signaling correlated with decreased expression of endothelial and angiogenic markers in kidney grafts as well as structural alterations. Because the number of glomerular endothelial cells expressing the LT beta R target nuclear factor kappa B-inducing kinase (NIK) decreased in the absence of a functional LT beta R, it was speculated that an LT beta R/NIK axis mediated the angiogenetic signals required for successful ectopic kidney organogenesis, given the established role of NIK in neovascularization. However, the transplantation of kidney rudiments in omenta of Nik(-/)(-) mice revealed that NIK is dispensable for ectopic kidney vascular integration and maturation. Finally, defective LT beta R signaling impaired compensatory glomerular adaptation to renal mass reduction, indicating that kidney regeneration approaches, besides whole kidney reconstruction, might benefit from the presence of LT beta R signals.