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Published on: February 4, 2015
Roles of angiopoietins in kidney development and disease
Adrian S Woolf1, Luigi Gnudi, David A Long
1Nephro-Urology Unit, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. a.woolf@ich.ucl.ac.uk
Abstract:
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.
Insights
Angiopoietins regulate blood vessel stability and survival in the kidney. Imbalances in angiopoietin signaling, particularly involving angiopoietin-1 and angiopoietin-2, contribute to kidney disease progression.
Area of Science:
- Nephrology
- Vascular Biology
- Molecular Biology
Background:
- Angiopoietins (Ang-1, Ang-2) are key regulators of vascular development and function.
- Tie-2 is a receptor tyrosine kinase crucial for endothelial cell survival and Tie-1 modulates this signaling.
- Vascular endothelial growth factor A and integrins further influence angiopoietin actions.
Purpose of the Study:
- To investigate the role of angiopoietins and their receptors in kidney development and disease.
- To elucidate the specific functions of Ang-1 and Ang-2 in renal endothelial cells and podocytes.
- To understand how angiopoietin signaling contributes to glomerular pathobiology.
Main Methods:
- Analysis of gene expression in developing and adult kidneys.
- Studies using knockout and transgenic mouse models (Ang-1 null, Ang-2 null, Ang-2 overexpression).
- Chimeric embryo analyses to assess Tie gene function in renal endothelial cells.
Main Results:
- Ang-1 is expressed in mature podocytes and mesenchyme; Ang-1 null embryos show vascular remodeling defects.
- Tie genes are essential for renal endothelial survival.
- Ang-2 is expressed in renal vascular cells and tubules; Ang-2 null mice exhibit altered pericyte coverage.
- Ang-1 therapy shows potential in tubulointerstitial disease models but may increase inflammation.
- Podocyte-specific Ang-2 overexpression induces glomerular endothelial apoptosis and albuminuria, with upregulation in glomerulopathies.
Conclusions:
- Angiopoietins play critical roles in renal vascular development, endothelial cell survival, and podocyte biology.
- Dysregulated angiopoietin signaling contributes to the pathogenesis of kidney diseases, including glomerulopathies.
- Targeting angiopoietin pathways may offer therapeutic strategies for kidney diseases, but requires careful consideration of potential side effects.
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