Abnormal angiogenesis is a well characterized complication in diabetic retinopathy and is now recognized as a feature of diabetic nephropathy. The primary growth factor driving the increased angiogenesis in diabetic retinopathy and nephropathy is vascular endothelial growth factor (VEGF). While VEGF is considered an important growth factor for maintaining glomerular capillary integrity and function, increased action of VEGF in diabetic renal disease may carry adverse consequences. Studies by our group suggest that the effects of VEGF are amplified in the setting of endothelial dysfunction and low nitric oxide (NO) levels, which are a common feature in the diabetic state. The lack of NO may amplify the effects of VEGF to induce inflammation (via effects on the macrophage) and may lead to dysregulation of the vasculature, exacerbating features of diabetic renal disease. In this review, we summarize how an “uncoupling” of the VEGF-NO axis may contribute to the pathology of the diabetic kidney. 1. Abnormal Angiogenesis Is a Characteristic Feature of Diabetic Nephropathy The first description documenting abnormal angiogenesis in the diabetic kidney is from a 1987 study by ？sterby and Nyberg [1]. These authors reported that patients with long-term type 1 diabetes showed an increase in capillaries in the renal biopsy that were both within and surrounding the glomeruli. Other investigators later demonstrated similar findings in type 2 diabetic patients with kidney disease [2, 3]. In these patients, 1–5% of glomerular capillaries were found to contain aberrant vessels. Interestingly, the abnormal vessels were also present in Bowman’s capsule or in the glomerular vascular pole, presenting as an “extra efferent arteriole” [1, 4]. A Japanese research group examined human kidney samples from 94 patients with diabetes and performed detailed analyses of serial sections using computer-generated three dimensional images [5]. They reported that the abnormal vessels were often found to be anastomosed to the lobular structure of the intraglomerular capillary network, mainly to afferent branches through the widened vascular hilus, while the distal end of the vessels was connected to the peritubular capillary. Morphologically the endothelial cells were often swollen early in the disease only to become shrunken as diabetes progressed [6, 7]. Another interesting finding was that the aberrant proliferation of blood vessels was not infrequent in diabetic patients even during the first two years of disease [5], indicating that the development of these vessels could occur in the
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