Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes. Role of oxidants and protein kinase-c activation

Abstract

Increases in leukostasis/monocyte adhesion to capillary endothelium (leukostasis) and decreases in retinal blood flow may be associated with the pathogenesis of diabetic retinopathy. The authors demonstrate that increases in leukostases are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia in a rat model using video fluorescein angiography and leukocyte fluorography. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rates, treatment with the antioxidant α-lipoic acid normalized the amount of leukostasis but not retinal blood flow. In contrast, treatment with D-α-tocopherol and protein kinase-C β (PKC β)-isoform inhibition prevented the increases in leukostasis and decreases in retinal blood flow in diabetic rates. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats but normalized by treatment with antioxidants α-lipoic acid and D-α-tocopherol and PKC β-isoform inhibiton. These findings suggest that leukostasis is associated with endothelial dysfunction, insulin resistance, and oxidative stress but is not related to retinal blood flow and is not sufficient to cause diabetic-like retinopathy. Also, treatment with PKC β inhibition is effective to normalize diabetes or hyperglycemicinduced PKC β-isoform activation and oxidative stress.—Hans E. Grossniklaus