Therapeutic Potential of Angiostatin in Diabetic Nephropathy

Abstract

Angiostatin is a proteolytic fragment of plasminogen and a potent angiogenic inhibitor. Previous studies have shown that angiostatin inhibits retinal neovascularization and reduces retinal vascular permeability in diabetic retinopathy. Here, it is reported for the first time that angiostatin is also implicated in diabetic nephropathy (DN). Angiostatin levels are dramatically decreased in the kidney of streptozotocin-induced diabetic rats. Consistently, diabetic kidneys also showed decreased expression and proteolytic activities of matrix metalloproteinase-2, an enzyme that releases angiostatin from plasminogen. Adenovirus-mediated delivery of angiostatin significantly alleviated albuminuria and attenuated the glomerular hypertrophy in diabetic rats. Moreover, angiostatin treatment downregulated the expression of vascular endothelial growth factor and TGF-␤1, two major pathogenic factors of DN, in diabetic kidneys. In cultured human mesangial cells, angiostatin blocked the overexpression of vascular endothelial growth factor and TGF-␤1 that were induced by high glucose while increasing the levels of pigment epithelium-derived factor, an endogenous inhibitor of DN. Moreover, angiostatin effectively inhibited the high-glucose-and TGF-␤1-induced overproduction of proinflammatory factors and extracellular matrix proteins via blockade of the Smad signaling pathway. These findings suggest that the decrease of angiostatin levels in diabetic kidney may contribute to the pathologic changes such as inflammation and fibrosis in DN. Therefore, angiostatin has therapeutic potential in DN as a result of its anti-inflammatory and antifibrosis activities.

Antiangiogenic Therapy in Diabetic Nephropathy

“…The article by Zhang et al in this issue shows that systemic adenoviral delivery of angiostatin to diabetic rats results in a significant reduction of albuminuria and glomerular hypertrophy (24). What is particularly interesting about this study is that the target of angiostatin is the mesangium, not the endothelium.…”

“…This observation seems to agree with the finding that extraendothelial targets for angiostatin, tumstatin, and endostatin have previously been documented (28 -30). Zhang et al further show that in vitro treatment of mesangial cells with angiostatin inhibited high glucose-induced VEGF, TGF-␤, monocyte chemoattractant protein-1, and fibronectin synthesis, whereas it enhanced the levels of pigment epithelium-derived factor, an endogenous antiangiogenic factor (24). This publication brings to light the possibility that targeting glomerular cell components, other than endothelial cells, with classical antiangiogenic factors might be beneficial in the treatment of diabetic nephropathy.…”

Angiostatin overexpression is associated with an improvement in chronic kidney injury by an anti-inflammatory mechanism

“…In kidney disease, levels of angiostatin are elevated in ischemia-reperfusion injury in which endothelial injury and capillary loss are prominent (3). On the other hand, adenoviral-mediated delivery of angiostatin alleviated albuminuria and glomerular hypertrophy in streptozocin-induced diabetic nephropathy (50). However, this is a model in which excessive VEGF-A expression and angiogenesis appear to be involved in the disease process (34).…”

Matrix Metalloproteinase-2 Dysregulation in Type 1 Diabetes

“…Rodent models of diabetes reveal decreased expression and/or proteolytic activity of MMP-2 in renal tissues (11)(12)(13). High glucose culture conditions also decrease MMP-2 secretion by mesangial cells in vitro (14).…”