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Podocyte-Specific Expression of Angiopoietin-2 Causes Proteinuria and Apoptosis of Glomerular Endothelia

Belinda Davis^*, Alessandra Dei Cas^*, David A. Long, Kathryn E. White, Anthea Hayward^*, Ching-Hsin Ku^*, Adrian S. Woolf, Rudolf Bilous, Giancarlo Viberti^* and Luigi Gnudi^*

^* Cardiovascular Division, King's College London School of Medicine, Guy's Hospital, King's College London, and Nephro-Urology Unit, Institute of Child Health, University College London, and Department of Diabetes and Metabolism, School of Clinical Medical Sciences, University of Newcastle, Newcastle, United Kingdom

Correspondence: Dr. Luigi Gnudi, Unit for Metabolic Medicine, Department of Diabetes and Endocrinology, 5th floor Thomas Guy House, Guy's Hospital, London SE1 9RT, UK. Phone: +44-20-71881939; Fax: +44-20-71880146; E-mail: luigi.gnudi{at}kcl.ac.uk

Received for publication October 6, 2006. Accepted for publication April 27, 2007.

Angiopoietin-2 (Ang-2) modulates embryonic vascular differentiation primarily by inhibiting the antiapoptotic effects of Ang-1 on endothelia that express the Tie-2 receptor. Ang-2 is transiently expressed by developing glomeruli but is downregulated with normal maturation. Glomerular Ang-2 expression is, however, markedly upregulated in animal models of diabetic nephropathy and glomerulonephritis, both leading causes of human chronic renal disease, affecting 10% of the world population. It was hypothesized that Ang-2 might have significant roles in the pathobiology of glomerular disease. Mice with inducible podocyte-specific Ang-2 overexpression were generated. When the transgene was induced in adults for up to 10 wk, mice had significant increases in both albuminuria and glomerular endothelial apoptosis, with significant decreases of both vascular endothelial growth factor-A and nephrin proteins, critical for maintenance of glomerular endothelia and filtration barrier functional integrity, respectively. There was, however, no significant change of systemic BP, creatinine clearance, or markers of renal fibrosis, and podocytes appeared structurally intact. In kidneys of young animals in which Ang-2 had been upregulated during organogenesis, increased apoptosis occurred in just-formed glomeruli. In vitro, short-term exposure of isolated wild-type murine glomeruli to exogenous Ang-2 led to decreased levels of vascular endothelial growth factor-A protein. These novel results provide insight into molecular mechanisms underlying proteinuric disorders, highlight potentially complex interactions between subsets of glomerular cells, and emphasize how a vascular growth factor that has critical roles in normal development may be harmful when re-expressed in the context of adult disease.

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