Low Ambient O₂Enhances Ureteric Bud Branching In Vitro

Abstract

Previously published online as an Organogenesis E-publication: http://www.landesbioscience.com/journals/organogenesis/abstract.php?id=1726 KEY WORDSmetanephroi, embryogenesis, fibroblast growth factor, vascular endothelial growth factor ACKNOWLEDGEMENTS T. Akimoto and E. Kusano were supported by in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, and Grants from Jin-Kenkyu-Kai. M.R. Hammerman was supported by grant DK 63379 from NIDDK. Research Paper Low Ambient O 2 Enhances Ureteric Bud Branching In Vitro ABSTRACTHypoxia exists widely in developing embryos where it may regulate blood vessel formation. VEGF and FGF2 produced in developing renal primordia (metanephroi) stimulate microvessel formation from embryonic thoracic aorta cultured under hypoxic conditions (HC) relative to room air (RA). The aim of the present study was to provide insight into the participation of hypoxia in a process that occurs concomitant with metanephros vascularization in vivo, ureteric bud (UB) branching. To this end, the arborization of the UB and growth of metanephroi were measured in metanephroi grown in serum-free organ culture for two days under RA or HC. When metanephroi were cultured under HC the arborization of UB was stimulated relative to RA. In the presence of anti-VEGF neutralizing antibody (αmVEGF), or anti-FGF2 neutralizing antibody (αhFGF2) UB branching was inhibited under both RA and HC. When both αmVEGF and αhFGF2 were added, the inhibition was enhanced. Addition of exogenous VEGF or FGF2 to cultures stimulated UB branching under RA and HC and addition of both stimulated it further. These findings provide evidence for roles of hypoxia and metanephric VEGF and FGF2, as regulators not only for vascularization but also for UB bud branching during renal organogenesis.

Hypoxia-inducible factor 1α regulates branching morphogenesis during kidney development

“…Previous research has shown that low ambient O 2 enhances ureteric bud branching in vitro [15], but the detailed mechanism is unknown. We investigated the effect of hypoxia on kidney development.…”

Role of hypoxia during nephrogenesis

“…The previously described 2005 study showed that VEGF and FGF2 played a role in UB branching in both oxygen tension conditions [48]. The 2015 study furthered this, demonstrating that hypoxic HIF activation increases paracrine VEGFA signaling to inhibit nephrogenesis but enhance tubulogenesis [50].…”

“…A 2005 study demonstrated that cultured E12 mouse kidney explants grown in 5% O 2 had more extensive ureteric branching than those cultured in 20% O 2 [48] (Table 1). Furthermore, E13 rat kidney explants cultured in 5% O 2 for 96 hours had significantly more UB branching than kidneys cultured in 21% O 2 [49].…”

Effect of Hypoxia on the Differentiation and the Self-Renewal of Metanephrogenic Mesenchymal Stem Cells

“…It has been reported that foetal hypoxia decreases nephron numbers and kidney weight [ 2 ]. However, it has been shown that hypoxia stimulates ureteric bud branching in vitro [ 3 ]. In this regard, an appropriately low O 2 tension is necessary for embryonic development.…”