Abnormal Angiogenesis in Diabetic Nephropathy
- 1Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, Colorado;
- 2Second Department of Internal Medicine, Asahikawa Medical College, Asahikawa, Japan;
- 3Nephro-Urology Unit, UCL Institute of Child Health, London, UK.
- Corresponding author: Takahiko Nakagawa, .
Diabetic retinopathy is the leading cause of blindness in the Western world (1) and is characterized by abnormal angiogenesis driven by several factors, including tissue ischemia and hyperglycemia. This abnormal angiogenesis results in new vessels that are often immature and play a pathological role in retinopathy, contributing to both vitreous hemorrhage and fibrosis (2). In addition, increased vascular permeability leading to plasma leakage accounts for the development of macula edema, disrupting visual function (2). These evidences have led to the development of several therapeutic strategies targeting angiogenesis in diabetic retinopathy (3).
Abnormal angiogenesis also occurs in diabetic nephropathy; therefore, the overriding question is whether new vessel formation in the kidney plays a pathological role in diabetic nephropathy similar to that observed in retinopathy. Intriguingly, the progression of both diabetic retinopathy and nephropathy is altered by vascular growth factor signaling through receptor tyrosine kinases, specifically involving the vascular endothelial growth factor (VEGF)-A and angiopoietin families. This review discusses abnormal angiogenesis and the role of both VEGF-A and angiopoietins in diabetic nephropathy.
Evidence of abnormal angiogenesis in diabetic nephropathy.
In 1987, Osterby and Nyberg (4) described abnormal blood vessels in glomeruli of patients with long-term type 1 diabetes, and later these findings were shown to occur in type 2 diabetic patients (5,6) (Fig. 1A). The abnormal vessels occupied 1–5% of glomerular capillary area, they were occasionally dilated, and the glomerular basement membrane adjacent to them was found to be focally extremely thin. Abnormal vessels were also present in Bowman's capsule or in the glomerular vascular pole, the latter of which could often be detected as an “extra efferent arteriole” (4,7). Min and Yamanaka (8) then performed detailed analyses of computer-generated three-dimensional images in 94 patients with diabetic nephropathy and found the presence of extravessels. Intriguingly, in this study the abnormal vessels anastomosed to …