Abstract
Purpose:
Tumor necrosis alpha converting enzyme (TACE/ADAM17) is an important regulator of inflammatory and neuroprotective responses because of its shedding ability towards cytokines, cytokine receptors, and adhesion molecules. We have previously shown that TACE/ADAM17 expression and activity were up-regulated in human and rat diabetic retinas. The purpose of the present study was to identify regulatory mechanisms of TACE-ADAM17 in the hyperglycemic-milieu particularly focusing on members of the rhomboid family of proteases, iRhom1 and 2, that have been shown to regulate TACE/ADAM17 maturation and translocation to the plasma membrane in competent cells.
Methods:
Streptozotocin-induced diabetic rats (STZ-rats) were kept diabetic for 8 and 12 weeks. Normoglycemic age-matched rats were used as control. Western blotting and immunohistochemical analyses were conducted to assess iRhom 1 and 2 and TACE/ADAM17 expression levels as well as immunolocalization in the rat retinas.<br />
Results:
Western blotting analysis revealed that hyperglycemia stimulated the expression of TACE/ADAM17 as well as of iRhom 1 and iRhom 2 in STZ-rat retinas as compared to normoglycemic age-matched control rats. In addition TACE/ADAM17 was immunolocalized around blood vessels and in cells of the inner nuclear layer. IRhom 1 immunoreactivity was highly expressed around blood vessels, whereas iRhom2 was mainly localized in cells of the inner nuclear layer.
Conclusions:
Our data show a positive induction of iRhom proteins in the diabetic retina and implicate the maturation process of TACE/ADAM17 in the pro-inflammatory events leading to neurovascular injury in the diabetic retina.<br />