Pigment epithelium-derived factor (PEDF) is the most potent inhibitor of angiogenesis, suggesting that loss of PEDF contributes to proliferative diabetic retinopathy. However, the role of PEDF against retinal vascular hyperpermeability remains to be elucidated. We investigated here whether and how PEDF could inhibit the advanced glycation end product (AGE) signaling to vascular hyperpermeability. Intravenous administration of AGEs to normal rats not only increased retinal vascular permeability by stimulating vascular endothelial growth factor (VEGF) expression but also decreased retinal PEDF levels. Simultaneous treatments with PEDF inhibited the AGE-elicited VEGF-mediated permeability by down-regulating mRNA levels of p22 phox and gp91 phox , membrane components of NADPH oxidase, and subsequently decreasing retinal levels of an oxidative stress marker, 8-hydroxydeoxyguanosine. PEDF also inhibited the AGE-induced vascular hyperpermeability evaluated by transendothelial electrical resistance by suppressing VEGF expression. Furthermore, PEDF decreased reactive oxygen species (ROS) generation in AGE-exposed endothelial cells by suppressing NADPH oxidase activity via down-regulation of mRNA levels of p22 PHOX and gp91 PHOX. This led to blockade of the AGE-elicited Ras activation and NF-B-dependent VEGF gene induction in endothelial cells. These results indicate that the central mechanism for PEDF inhibition of the AGE signaling to vascular permeability is by suppression of NADPH oxidasemediated ROS generation and subsequent VEGF expression. Substitution of PEDF may offer a promising strategy for halting the development of diabetic retinopathy.
Male rats of WBN/Kob strain are one of the diabetic model animals and develop long-lasting diabetic symptoms and some complications from about 40 weeks of age without any treatment. A single intravenous dose of alloxan, a non-genotoxic diabetogenic chemical, frequently induced proliferative lesions of squamous epithelium in tongue, esophagus and forestomach of male and female WBN/Kob rats, and hastened the onset and acceleration of diabetic conditions. Histopathologically, proliferative changes of squamous cell of forestomach varied with the severity of hyperplasia in alloxan-treated rats (100% of 31 males and 94.1% of 17 females) and progressed to SCC in approximately 20% of all rats. Metastasis to regional lymph nodes was also observed in two cases. Proliferative changes were most severe in the forestomach and were constantly accompanied with chronic suppurative inflammation of the mucosal epithelium with infection of filamentous fungi and/or bacterial colonies. In contrast, forestomach of the spontaneously diabetic male rats showed only slight hyperplasia of the mucosal epithelium confined to the limiting ridge in approximately 30% of the cases. All non-diabetic female rats showed neither proliferative changes nor the inflammatory process in the mucosa. Immunohistochemically, COX-2 and iNOS were positive in these chronic suppurative inflammatory lesions accompanied by proliferative squamous epithelium. From these results, it is suggested that chronic inflammatory processes play an important role in the pathogenesis of alloxan-induced SCC. (1) The diabetic conditions are characterized by low-level blood insulin, (2) and glucosuria from approximately 40 weeks of age and development of various diabetic complications such as peripheral neuropathy, (3,4) nephropathy (5) and retinopathy (6) in advanced age. Furthermore, these rats had been reported to be an animal model with successful induction of gastric cancer in the lesser curvature of stomach, a common occurrence site of human gastric carcinoma, by the treatment of carcinogens. (7) However, no spontaneous proliferative lesions were described in the alimentary tracts even in the older rats of this strain.In the serial studies for the analyses of pathogenesis of diabetic complications, male and female WBN/Kob rats were given a single dose of alloxan in order to accelerate the diabetic condition. A rat autopsy 50 weeks after treatment with alloxan presented a case of SCC in the forestomach.Alloxan is one of the chemicals that induce loss of insulinproducing islet β-cells and cause a hypoinsulinemic condition and resultant diabetes mellitus in animals. This effect is thought to be mediated by a sequence of redox reactions involving the production of superoxide anion radicals in or near the β-cells. As a neoplastic lesion caused by alloxan injection, β-cell tumors leading to primary injury to the pancreatic islet have been reported in a few rats, (11) but there were no reports of alloxaninduced tumors in organs other than the pancreas. Alloxan is not mutagenic, jud...
Rodent models of diabetes develop a slowing of nerve conduction velocity and mild axonal atrophy, but generally lack overt degenerative neuropathy. Spontaneously diabetic Wistar Bonn Kobori (WBN/Kob) rats develop severe diabetic peripheral motor neuropathy with a slowing of nerve conduction velocity. We examined the effect of glycemic control, using insulin implant, on neuropathic changes in these rats. Animals were divided into 2 groups: WBN group (spontaneously occurring diabetes rats) and WBN + insulin group (spontaneously occurring diabetes rats treated with insulin implants until 90 weeks of age). Conduction velocity was measured in sciatic–tibial motor nerves. These nerves also underwent qualitative and quantitative histomorphologic analysis. Mild to severe hyperglycemia (>200 mg/dl) and glycosuria (>100 mg/dl) were observed in the WBN group. In contrast, the blood glucose level of the WBN + insulin group fluctuated between normoglycemia (<200 mg/dl) and hyperglycemia. Conduction velocity significantly decreased in WBN group compared with WBN + insulin group. Morphologic analysis of the sciatic and tibial nerves of WBN group showed severe changes, including axonal degeneration, myelin distention, endoneurial fibrosis and microangiopathy. Insulin treatment corrected these changes without microangiopathy. These results suggest that insulin could decrease axonal atrophy and myelin distension of peripheral nerve in diabetic WBN/Kob rats. Observation of WBN/Kob rats revealed changes of axon, myelin and capillary caused by diabetes, thus indicating that this animal is a suitable model for investigating diabetic peripheral neuropathy.
Diabetic patients are predisposed to periodontal disease as well as dental caries; however, there are contradictory reports about the possible association between dental caries and diabetes. Thus, the authors set out to determine whether diabetes affects onset of dental caries and periodontal disease and to clarify whether dental caries and periodontal disease are associated with each other in diabetic db/db mice. Oral tissue was examined from 68 male mice (diabetic db/db and nondiabetic db/+; aged 20, 30, 40, and 50 weeks) and 20 female mice (db/db and db/+; aged 50 weeks). Macroscopically, caries were seen developing in the diabetic mice by 20 weeks of age. The number of teeth with dental lesions increased with age in the db/db mice at a significantly higher incidence than that of db/+ mice. Histologically, dental caries were detected in 30 of 120 molars in 17 of 20 db/db mice at 50 weeks of age and in 4 of 108 molars in 4 of 18 db/+ mice of the same age. The severity of dental caries in db/db mice was significantly higher than it was in db/+ mice. Dental caries were a primary change that led to bacterial gingivitis and pulpitis. These lesions spread to the dental root and periodontal connective tissue through the apical foramen. Apical periodontitis was more frequent and severe when occurring in close association with dental caries. In conclusion, there is a strong relationship between diabetes and dental caries, but in this model, it is highly probable that the onset of periodontal disease was a secondary change resulting from dental caries.
The relationship between hypertension and diabetic peripheral neuropathy (DPN) has recently been reported in clinical research, but it remains unclear whether hypertension is a risk factor for DPN. To investigate the effects of hypertension on DPN, we analyzed morphological features of peripheral nerves in diabetic rats with hypertension. Male WBN/Kob rats were divided into 2 groups: alloxan-induced diabetic rats with deoxycorticosterone acetate-salt (DOCA-salt) treatment (ADN group) and nondiabetic rats with DOCA-salt treatment (DN group). Sciatic, tibial (motor) and sural (sensory) nerves were subjected to qualitative and quantitative histomorphological analysis. Systolic blood pressure in the two groups exhibited a higher value (>140 mmHg), but there was no significant difference between the two groups. Endoneurial blood vessels in both groups presented endothelial hypertrophy and narrowing of the vascular lumen. Electron microscopically, duplication of basal lamina surrounding the endothelium and pericyte of the endoneurial vessels was observed, and this lesion appeared to be more frequent and severe in the ADN group than the DN group. Many nerve fibers of the ADN and DN groups showed an almost normal appearance, whereas morphometrical analysis of the tibial nerve showed a significant shift to smaller fiber and myelin sizes in the ADN group compared with DN group. In sural nerve, the fiber and axon-size significantly shifted to a smaller size in ADN group compared with the DN group. These results suggest that combined diabetes and hypertension could induce mild peripheral nerve lesions with vascular changes.
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