Roles of angiopoietins in kidney development and disease.
Angiopoietins are a family of growth factors, the best studied being angiopoietin 1 (Ang-1), which binds to and tyrosine-phosphorylates endothelial Tie-2, causing enhanced survival and cell-cell stabilization. Ang-2 and Tie-1 downregulate Ang-1-induced Tie-2 signaling, and angiopoietin actions are further modified by vascular endothelial growth factor A and integrins. Metanephric capillaries express Tie genes, whereas metanephric mesenchyme, maturing tubules, and mature podocytes express Ang-1. Ang-1 null embryos begin to form blood vessels, but subsequent vascular remodeling fails, and analyses of chimeric wild-type/Tie null mutant embryos show that Tie genes are needed for renal endothelial survival. Ang-2 is transiently expressed in renal arterial smooth muscle and mesangial cells, and tubules around adult vasa rectae express Ang-2. Ang-2 null mice have increased pericytes around kidney cortical peritubular capillaries, perhaps an indirect consequence of upregulated Tie-2 signaling. Ang-1 therapies attenuate peritubular capillary loss in adult models of tubulointerstitial disease, although, in one study, this was accompanied by enhanced inflammation and fibrosis. Podocyte-directed Ang-2 transgenic overexpression causes glomerular endothelial apoptosis, downregulated nephrin expression, and increased albuminuria, and glomerular Ang-2 is upregulated in hyperglycemic and immune-mediated glomerulopathies. Thus, angiopoietins affect podocyte as well as glomerular endothelial biology, and imbalanced angiopoietin signaling contributes to glomerular pathobiology.
Woolf
Adrian S
AS
Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. a.woolf@ich.ucl.ac.uk
Gnudi
Luigi
L
Long
David A
DA
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D042682:Angiopoietins / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction; D019076:Transgenes
D042702:Angiopoietin-2; D042682:Angiopoietins