Author(s): Khoury CC, Ziyadeh FN, Khoury CC, Ziyadeh FN
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Abstract Diabetic nephropathy (DN) is in essence a microvascular disease that develops as a result of a confluence of hemodynamic and metabolic perturbations. Angiogenic factors are prime candidates to explain the vascular and pathologic findings of DN; however, analysis of their pathophysiology shows that they have a constellation of effects on the glomerulus that go beyond angiogenesis. Vascular endothelial growth factor (VEGF) is an exemplary candidate for fulfilling the criteria for Koch's postulate as an etiologic agent of the glomerulopathy in diabetes. Its expression and signaling in the kidney are amplified early on in the diabetic state. Moreover, counteracting its effects reverses the albuminuria and other hemodynamic and structural features of experimental DN. Finally, experimental overexpression of VEGF in adult mice replicates several aspects of diabetic kidney disease. Under the influence of a variety of diabetic mediators, the podocyte becomes the main source of increased expression of VEGF in the kidney. The cytokine then exerts its multitude of effects in an autocrine fashion on the podocyte itself, on the endothelial cell in a paracrine manner, and finally contributes to macrophage recruitment acting as a chemokine. The angiopoietins consist primarily of two main factors acting in contrast to each other: Ang1--an antiangiogenic ligand, and Ang2--its competitive inhibitor. Both, however, seem to have important roles in the maintenance of glomerular homeostasis. Diabetes disrupts the tight balance that controls angiopoietin expression and functions and decreases theAng1/Ang2 ratio. The end physiologic result seems to be dependent on the concomitant VEGF changes in the kidney. Because of the intricacy of their control, angiogenic factors are difficult to manipulate therapeutically. However, they remain valid target points for the treatment of DN. Copyright © 2011 S. Karger AG, Basel.
This article was published in Contrib Nephrol
and referenced in Advances in Oncology Research and Treatments