No abstract

We previously have found that advanced glycation end products (AGE), senescent macroproteins formed at an accelerated rate in diabetes, arise in vivo not only from glucose but also from reducing sugars. Furthermore, we recently have shown that glyceraldehyde- and glycolaldehyde-derived AGE (glycer- and glycol-AGE) are mainly involved in loss of pericytes, the earliest histopathological hallmark of diabetic retinopathy. However, the effects of these AGE proteins on angiogenesis, another vascular derangement in diabetic retinopathy, remain to be elucidated. In this study, we investigated whether these AGE proteins elicit changes in cultured endothelial cells that are associated with angiogenesis. When human skin microvascular endothelial cells (EC) were cultured with glycer-AGE or glycol-AGE, growth and tube formation of EC, the key steps of angiogenesis, were significantly stimulated. The AGE-induced growth stimulation was significantly enhanced in AGE receptor (RAGE)-overexpressed EC. Furthermore, AGE increased transcriptional activity of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) and then up-regulated mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in EC. Cerivastatin, a hydroxymethylglutaryl CoA reductase inhibitor; pyrrolidinedithiocarbamate; or curcumin was found to completely prevent the AGE-induced increase in NF-kB and AP-1 activity, VEGF mRNA up-regulation, and the resultant increase in DNA synthesis in microvascular EC. These results suggest that the AGE-RAGE interaction elicited angiogenesis through the transcriptional activation of the VEGF gene via NF-kB and AP-1 factors. By blocking AGE-RAGE signaling pathways, cerivastatin might be a promising remedy for treating patients with proliferative diabetic retinopathy.

No abstract

Advanced glycation end products (AGEs) are linked with the development of diabetic retinopathy; however, the pathogenic mechanisms are poorly defined. Vascular endothelial growth factor (VEGF) levels are increased in ischemic and nonischemic diabetic retina, and VEGF is required for the development of retinal and iris neovascularization. Moreover, VEGF alone can induce much of the concomitant pathology of diabetic retinopathy. In this study, we found that AGEs increased VEGF mRNA levels in the ganglion, inner nuclear, and retinal pigment epithelial (RPE) cell layers of the rat retina. In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells. The AGE-induced increases in VEGF expression were dose- and time-dependent, inhibited by antioxidants, and additive with hypoxia. Use of an anti-VEGF antibody blocked the capillary endothelial cell proliferation induced by the conditioned media of AGE-treated cells. AGEs may participate in the pathogenesis of diabetic retinopathy through their ability to increase retinal VEGF gene expression.

No abstract

Advanced glycation end products (AGEs) are linked with the development of diabetic retinopathy; however, the pathogenic mechanisms are poorly defined. Vascular endothelial growth factor (VEGF) levels are increased in ischemic and nonischemic diabetic retina, and VEGF is required for the development of retinal and iris neovascularization. Moreover, VEGF alone can induce much of the concomitant pathology of diabetic retinopathy. In this study, we found that AGEs increased VEGF mRNA levels in the ganglion, inner nuclear, and retinal pigment epithelial (RPE) cell layers of the rat retina. In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells. The AGE-induced increases in VEGF expression were dose-and time-dependent, inhibited by antioxidants, and additive with hypoxia. Use of an anti-VEGF antibody blocked the capillary endothelial cell proliferation induced by the conditioned media of AGE-treated cells. AGEs may participate in the pathogenesis of diabetic retinopathy through their ability to increase retinal VEGF gene expression.

Androgens are well known for their many functions in promoting sexual differentiation and the induction of the male phenotype. In the male, the two endogenous androgens most active in promoting these effects are testosterone and nonaromatizable 5a-dihydrotestosterone (DHT). They also play important roles in the regulation of bone metabolism. The direct effects of androgen on bone cells is suggested by the presence of androgen receptors (AR) on several human and rat established osteoblast cell lines as well as normal human osteoblast cells (HOB).1) Androgens increase rates of cellular proliferation and differentiation of osteoblasts, increase TGF-b levels, increase production of matrix proteins and inhibit osteoclast function.2,3) A role of androgens in skeletal regulation is substantiated by numerous studies in human and rodents, demonstrating that chemical or surgical castration, as well as untreated hypogonadism in men and androgen deficiency in women with hypopituitarism, lead to accelerated bone loss.2,4-7) Importantly, the deleterious effects of these conditions on bone can be reversed by treatment with androgens.One apparently unique effect of androgens is to increase periosteal bone formation in cortical bone, while estrogens depress it.8) This reflects a major gender difference in bone size, which is one of important factors determining the bone strength. A number of studies provide the proof of principle that androgens are osteoanabolic in rodents, women and men. Nonaromatizable DHT increased cortical bone volume and periosteal bone formation rates when administrated to ovariectomized rats.9) The synthetic anabolic steroids, such as nandrolone decanoate or stanozolol, have been shown to increase bone mass in postmenopausal women, possibly via stimulation of bone formation.10,11) Beneficial anabolic effects of androgens on bone in postmenopausal osteoporosis are well-documented in recent studies using combined testosterone and estrogen administration.12,13) On the other hand, bone resorption inhibitors such as estrogens, bisphosphonates, selective estrogen receptor modulators (SERMs) and calcitonin, which are still first line of treatment/prevention of osteoporosis, are not sufficient to restore bone mass for patients who have already lost a significant amount of bone. In addition, bone turnover rate differs from site to site; higher in the cancellous bone of vertebrae than in the cortical bone of the long bones. Therefore, osteoanabolic agents, which increase cortical/periosteal bone formation and bone mass of long bones, would address unmet need in the treatment of osteoporosis especially for patients with high risk of fractures. The osteoanabolic agents also complement the bone resorption inhibitors that target the cancellous bones, leading to a biomechanically favorable bone structure. 14)Despite the beneficial effects of androgens in therapies for osteoporosis, hypogonadism and other androgen deficient diseases, clinical use of them has been limited because of the undesirable virilizing (acne, hirsu...

The results suggest that AGE inhibits de novo protein synthesis and stimulates TGF-beta mRNA expression in proximal tubular epithelial cells through overgeneration of intracellular ROS. Thus, AGE are involved in the pathogenesis of tubular injury in diabetic nephropathy.