Angiopoietins: vascular growth factors looking for roles in glomeruli

Abstract

The present review highlights general advances concerning angiopoietin (Ang) biology and then focuses on possible roles of these molecules within healthy and diseased glomeruli. Early experiments showed that Ang1 stabilizes newly formed vessels and reduces vascular permeability, with Ang2 blocking Ang1 activation of the Tie2 receptor. Recent studies found that Ang2 can directly stimulate Tie2 and that both Ang1 and Ang2 can be pro-inflammatory. Ang/Tie2 biology is modified by vascular endothelial growth factor and by a related receptor, Tie1. In health, Tie1 and Tie2 are expressed by glomerular endothelia, whereas podocytes express Ang1. In-vitro studies show that exogenous Ang1 enhances capillary formation within developing glomeruli. Ang1 applied to glomerular endothelial monolayers increases transcellular electrical resistance and reduces albumin transit, effects associated with enhanced cell surface glycocalyx. Glomerular Ang2 expression increases in diabetic glomerulopathy and immune-mediated glomerulonephritis. When glomerular Ang2 is experimentally upregulated in healthy mice, endothelial apoptosis and albuminuria increase, and vascular endothelial growth factor and nephrin are downregulated. Experimental evidence does not yet exist to allow us to assign definitive in-vivo glomerular functions to the angiopoietins. Key experiments will be to study the effects of downregulating Ang1 in healthy animals and downregulating Ang2 levels in glomerular disease.