Diabetes Can Alter the Signal Transduction Pathways in the Lens of Rats

Abstract

Diabetes is known to affect cataract formation by means of osmotic stress induced by activated aldose reductase in the sorbitol pathway. In addition, alterations in the bioavailability of numerous extralenticular growth factors has been reported and shown to result in various consequences. We have found that the basic fibroblast growth factor (bFGF) accumulates in the vitreous humor of 3-and 8-week diabetic rats. Consequently, the associating signal transduction cascades were severely disrupted, including upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and the common stress-associated mitogen-activated protein kinases p38 and SAPK/JNK. Conversely, under diabetic condition, we observed a dramatic inhibition of phosphatidylinositol-3 kinase activity in lenses obtained from the same animal. Rats treated with the aldose reductase inhibitor AL01576 for the duration of the diabetic condition showed that the diabetes-induced lenticular signaling alterations were normalized, comparable to controls. However, treatment of AL01576 in vitro was ineffective at normalizing the altered constituents in extracted diabetic vitreous after the onset of diabetes. The effect of AL01576 in the high galactoseinduced cataract model in vitro was also examined. Administration of AL01576 to lens organ culture normalized the aberrant signaling effects and morphological characteristics associated with in vitro sugar cataract formation. In conclusion, our findings demonstrate diabetes-associated alterations in the lens signal transduction parameters and the effectiveness of AL01576 at normalizing such alterations. The causes for these alterations can be attributed to elevated vitreal bFGF in conjunction with osmotic stress and associated attenuation in redox status of the lens.

Effect of an Aldose Reductase Inhibitor on Alveolar Bone Loss Associated with Periodontitis in Diabetic Rats

“…This dose has previously been established to prevent ophthalmic effects in diabetic and galactosemic rats. [25][26][27][28][29] Lens changes were also absent in the nondiabetic controls.…”

Water extract of Aralia elata prevents cataractogenesis in vitro and in vivo

“…Consequently, the associating signal transduction cascades are severely disrupted. These included the up-regulation of the phosphorylation of extracellular signal-regulated kinase (ERK), and of the common stress-associated mitogen-activated protein kinases p38 and SAPK/JNK (Zatechka et al, 2003). It was also reported that a 1:1 mixture of Phellodendron amurense and Aralia elata has the ability to increase glycogen contents in hepatocytes, possibly by stimulating PI3-kinase and ERK2 (Kim et al, 1998).…”

Protein Kinase C-γ Activation in the Early Streptozotocin Diabetic Rat Lens

“…20,24,49 High blood glucose-induced sorbitol accumulation would generate osmotic stress, which would subsequently activate the ERK1/2 and p38/JNK pathways in the prolonged (∼3 weeks and longer) streptozotocin diabetic rat lenses. 22 Activation of these pathways regulates glucose transporters GLUT1 and GLUT3. 40 Inactive GLUT1 and GLUT3 are stored in cytoplasmic pools.…”

“…22 To test if the inhibition of gap junctions by activation of PKC-γ causes disruption of cellular signaling in the lenses of VHG diabetic rats, we determined activation of ERK1/2 and caspase-3, a cell apoptotic stress marker. Activation of ERK1/2 occurs through phosphorylation of Thr202/Tyr204.…”

“…Diabetes induces changes in many cellular pathways, including activation of protein kinase C-β (PKC-β) and PKC-δ, decreases in levels of growth factors, (e.g., IGF-1), and disruption of gap junctions in cardiovascular tissues, retina, and lens. 12,13,22,23 Inhibition of the polyol pathway enzyme, aldose reductase, prevents lens epithelial cells from hyperglycemia-induced PKC activation and caspase-3-dependent apoptosis. 24 Yet, the mechanism of diabetic cataractogenesis and the role of PKC-γ are not well understood.…”