Increased Vascular Permeability in Spontaneously Diabetic BB/W Rats and in Rats With Mild Versus Severe Streptozocin-Induced Diabetes: Prevention by Aldose Reductase Inhibitors and Castration
Authors: Williamson Joseph R , Chang Katherine , Tilton Ronald G , Prater Cheryl , Jeffrey Jay R , Weigel Carolyne , Sherman William R , Eades Donald M , Kilo Charles 
Published: September 2013

125I-labeled albumin permeation (IAP) has been assessed in various tissues in spontaneously diabetic insulin-dependent female BB/W rats and in male Sprague-Dawley rats with severe or mild forms of streptozocin-induced diabetes (SS-D and MS-D, respectively). In BB/W diabetic rats and in rats with SS-D, indices of IAP were significantly increased in tissues and vessels predisposed to diabetic vascular disease in humans, including the eyes (anterior uvea, posterior uvea, and retina), sciatic nerve, aorta, kidney, and new vessels formed after induction of diabetes. No evidence of increased IAP was observed in heart, brain, testes, or skeletal muscle in BB/W or SS-D rats. In MS-D rats, indices of IAP were increased only in the kidney and in new vessels formed after the onset of diabetes.

Marked tissue differences were observed in the effects of two structurally different aldose reductase inhibitors (sorbinil and tolrestat) and of castration on diabetes-induced increases in IAP and in tissue levels of polyols in SS-D rats. Both aldose reductase inhibitors and castration completely prevented diabetes-induced increases in IAP in new vessels and in sciatic nerve in BB/W and SS-D rats. Both aldose reductase inhibitors also markedly decreased IAP in the anterior uvea (∼85%), posterior uvea (∼65-75%), retina (∼65-70%), and kidney (∼70-100%); castration reduced IAP in the anterior uvea (∼55%), kidney (∼50%), and retina (∼30%) but had no effect on the posterior uvea. The diabetes-induced increases in IAP in the aorta were reduced only slightly (∼20%) by aldose reductase inhibitors and castration.

In SS-D rats, tissue polyol levels were markedly increased in sciatic nerve, retina, anterior uvea, and posterior uvea but not in the aorta. Castration significantly reduced polyol levels only in the sciatic nerve and retina, whereas both aldose reductase inhibitors markedly decreased polyol levels in anterior and posterior uvea and in sciatic nerve and retina.

These observations demonstrate that 1) the most characteristic functional alteration in vessels in human diabetics, i.e., increased vascular permeability, is evident in rats with diabetes of only 3 wk duration; 2) the most marked increases in IAP in the diabetic rat occur in vessels associated with clinically significant vascular disease in human diabetics; 3) even very mild diabetes is associated with increased IAP in the kidney and in new vessels induced by angiogenesis in the diabetic milieu; 4) diabetes-induced increases in IAP in all tissues examined are aldose reductase-linked phenomena and, with the exception of the posterior uvea, are modulated by sex steroids; and 5) the extent to which diabetes-induced increases in IAP are modulated by sex steroids and reduced or completely prevented by aldose reductase inhibitors varies markedly in different vascular beds.