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【medical-news】哈佛大学Joslin糖尿病中心发现糖尿

Novel Pathway Uncovered in Diabetic Vision Loss

In people with diabetes, macular edema is a leading cause of moderate to severe vision loss. The immediate cause is increased retinal vascular permeability that allows infiltration of serum proteins and lipids into the macula. This leakage can result in thickening and interference with photoreceptor function. A study by Ben-Bo Gao, research fellow in the laboratory of Edward Feener, an HMS assistant professor of medicine at Joslin Diabetes Center, identifies a novel pathway involved in development of retinal vascular permeability and activation of the kallikrein–kinin system. The findings appear in the Jan. 28 online edition of Nature Medicine. (Nature Medicine - 13, 181 - 188 (2007)
).

Using mass spectrometry–based proteomics, Gao, Feener, and their colleagues identified 27 proteins from vitreous samples of patients with diabetic retinopathy whose levels were elevated over those of the same proteins in non-diabetic controls. The researchers homed in on carbonic anhydrase-1 (CA-1) for further study since its level was 15-fold higher than that in samples from non-diabetic controls. The scientists predicted that an overabundance of its activity in the vitreous might interfere with extracellular pH homeostasis in the neuroretina.

Intravitreal injection of human CA-1 into rats, at concentrations much lower (2 ng/µl) than those measured in vitreous samples of diabetic patients (10–50 ng/µl) led to leakage of marker fluorescein dye into the intraretinal space. This was direct evidence that CA-1, in trace quantities, increases retinal vascular permeability and induces leakage. Examination of retinal ultrastructure showed intraretinal thickening, which was similar to clinically evident edema. Screening of protease pathways led the researchers to implicate kallikrein–kinin activation in this process.

The researchers propose that retinal hemorrhage causes the release of CA-1 into the vitreous fluid from lysed red blood cells. Extracellular CA-1 mediates the hydration of CO2 released from the photoreceptor cells to bicarbonate within the vitreous. This process is normally catalyzed within the lumen of blood vessels and facilitates the removal of CO2 from the retina. The accumulated bicarbonate in the vitreous causes increasingly alkaline conditions that precede activation of the kallikrein pathway, a component of the innate inflammatory response. The outcome is the generation of bradykinin, which increases vascular permeability and inflammation.
Although retinal hemorrhage is a common finding in people with diabetic retinopathy, Feener said, the significance of this bleeding in the pathogenesis of the disorder had not been appreciated. In essence, these experiments uncover a new pathway whereby retinal hemorrhage leads to the release of CA-1 into the vitreous, which induces kallikrein–kinin activation with a consequent increase in retinal vascular permeability and edema.

There are 15 isoforms of CA in humans, and use of nonspecific CA inhibitors to treat conditions such as glaucoma often target more than one of them. The identification of extracellular CA-1 and its downstream mechanisms of action in diabetic retinopathy could enable development of targeted inhibitors for its treatment. Further studies in Feener’s laboratory are aimed at elucidating the role of other proteins occurring in the vitreous as a result of diabetic complications.

—Amita Joshi
http://focus.hms.harvard.edu/2007/020907/research_briefs.shtml 本人已认领该文编译,48小时后若未提交译文,请其他战友自由认领。 Novel Pathway Uncovered in Diabetic Vision Loss
糖尿病视力丧失的新机制
In people with diabetes, macular edema is a leading cause of moderate to severe vision loss. The immediate cause is increased retinal vascular permeability that allows infiltration of serum proteins and lipids into the macula. This leakage can result in thickening and interference with photoreceptor function. A study by Ben-Bo Gao, research fellow in the laboratory of Edward Feener, an HMS assistant professor of medicine at Joslin Diabetes Center, identifies a novel pathway involved in development of retinal vascular permeability and activation of the kallikrein–kinin system. The findings appear in the Jan. 28 online edition of Nature Medicine. (Nature Medicine - 13, 181 - 188 (2007)
).
黄斑水肿是导致糖尿病病人视力中度至重度丧失的主要原因。视网膜血管通透性增高引起的血浆蛋白和脂质渗透进入黄斑是导致黄斑水肿直接原因,这种渗漏作用导致视网膜的增厚以及感光功能受到影响。高本波博士是Edward Feener实验室的研究人员,Feener博士是哈佛大学医学院Joslin糖尿病中心的医学助理教授。高本波博士进行的一项研究中发现与视网膜血管通透性增高及激肽释放酶-激肽系统的激活有关的新的机制。这一研究结果已经在1月28日的《自然医学》杂志上刊登。

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作者:admin@医学,生命科学    2011-06-22 05:12
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