Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation.
Increases in leukostasis/monocyte adhesion to the capillary endothelium (leukostasis) and decreases in retinal blood flow may be causally associated and are implicated in the pathogenesis of diabetic retinopathy. In this study, we demonstrate that increases in leukostasis are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rats, treatment with the antioxidant alpha-lipoic acid normalized the amount of leukostasis but not retinal blood flow. In contrast, treatment with D-alpha-tocopherol and protein kinase-C beta-isoform inhibition (LY333531) prevented the increases in leukostasis and decreases in retinal blood flow in diabetic rats. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats, but normalized by treatment with antioxidants alpha-lipoic acid and D-alpha-tocopherol and, surprisingly, PKC beta-isoform inhibition. 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. Moreover, treatment with PKC beta inhibition is effective to normalize diabetes or hyperglycemia-induced PKC beta-isoform activation and oxidative stress.
Abiko
Toru
T
Research Division, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA.
Abiko
Atsuko
A
Clermont
Allen C
AC
Shoelson
Brett
B
Horio
Naoichi
N
Takahashi
Junichi
J
Adamis
Anthony P
AP
King
George L
GL
Bursell
Sven-Erik
SE
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001783:Blood Flow Velocity; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003930:Diabetic Retinopathy / Q000209:etiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000097:blood; D007211:Indoles / Q000627:therapeutic use; D007333:Insulin Resistance; D018921:Leukostasis / Q000188:drug therapy; D008297:Male; D008301:Maleimides / Q000627:therapeutic use; D008833:Microcirculation / Q000503:physiopathology; D008863:Microspheres; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D064546:Protein Kinase C beta; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D020318:Rats, Long-Evans; D011924:Rats, Zucker; D012160:Retina / Q000473:pathology*; D012171:Retinal Vessels / Q000473:pathology / Q000503:physiopathology; D008063:Thioctic Acid / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000627:therapeutic use
D000975:Antioxidants; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D016877:Oxidants; C099154:ruboxistaurin; D008063:Thioctic Acid; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D024502:alpha-Tocopherol