Endothelial signaling in kidney morphogenesis: a role for hemodynamic forces

The local presence of endothelial cells seems necessary for proper embryonic development of several organs. However, the signals involved are unknown. The glomerulus is generated by the coalescence of podocytes around an ingrowing capillary and is the site of blood ultrafiltration. In the absence of vessels, glomerular assembly does not occur. We describe mutations in the zebrafish that prevent glomerulogenesis. All mutants display cardiac dysfunction. Pharmacological interference with cardiac output and focal laser occlusion of the vessel similarly prevent glomerular formation. The unifying feature of all these perturbations is absence of blood flow. We find that expression of matrix metalloproteinase-2 (MMP-2), known in other systems to be regulated in a stretch-responsive manner, is in renal endothelial cells and is regulated by flow, suggesting that an MMP-2-sensitive event may be downstream of the flow-related signal. In support of this, blockade of MMP-2 activity by injection of TIMP-2 does not perturb circulation but does prevent glomerular assembly. Thus, vascular flow is required for glomerular assembly, most probably acting via a stretch-responsive signaling system in the vessel wall.