Effects of diabetes on retinal pigment epithelial cell proliferation and mitogen-activated protein kinase signaling in dark Agouti rats

Abstract

Although diabetes induces retinopathy its effects on retinal pigment epithelium (RPE) are not clearly known. The present study investigated the effects of streptozotocin-induced diabetes on RPE cell proliferation and the expression of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinases (JNKs) in rats. The bromodeoxyuridine immunohistochemistry revealed diabetes induced RPE cell proliferation at the end of first and second weeks in dark Agouti rats and at the end of first week in Wistar rats, but it inhibited the proliferation in both strains at the end of fifth week (P<0.05). A further analysis at the end of second week in the dark Agouti rats showed the cell proliferation, but not apoptosis, in association with an increase in ERK1/2 expression (P<0.05). However, the increased ERK level did not affect the expression of one of its substrates, the transcription factor c-Fos, suggesting that this protein has no role in the induction of the RPE cell proliferation. On the other hand, although total JNKs showed a decrease in the diabetic group (P<0.05), the JNKp46 isoform was increased and the JNKp54 isoform was decreased, but without any effects on one of their substrates, the transcription factor, c-Myc. Our results indicate that the RPE cell proliferation in diabetic rats may be mediated through mitogen-activated protein kinases. Thus, modulation of mitogen-activated protein kinases signaling may be a putative therapeutic option to alleviate the genesis of diabetes-induced retinal disruptions including retinopathy.

Keywords: Apoptosis; Blood–retinal barrier; Cell proliferation; Diabetic retinopathy; Extracellular-signal regulated kinases; Mitogen-activated protein kinases; c-Jun-N terminal kinases.