Curcumin Attenuates Retinal Vascular Leakage by Inhibiting Calcium/Calmodulin-Dependent Protein Kinase II Activity in Streptozotocin-Induced Diabetes

Abstract

Background: Curcumin possesses many pharmacological properties including anti-inflammatory effects. Although prior studies indicate that curcumin has beneficial effects for diabetic retinopathy, the mechanism of action is not known. To address this issue, we investigated the effect of curcumin against diabetes-induced retinal vascular damage and its mechanism of action by using cultured retinal Müller cells stimulated with high glucose. Methods: We studied the effects of curcumin in vivo in the retinas of rats rendered diabetic by streptozotocin and in vitro in Müller cells stimulated with high glucose. We administered curcumin, or KN93, an inhibitor of calcium/calmodulin dependent protein kinase II (CaMKII), or saline vehicle to experimental animals on a daily basis for 12 weeks. Primary cultures of rat Müller cells were incubated with normal glucose or high glucose, with or without curcumin, KN93, or pyrrolidine dithiocarbamate (PDTC), an inhibitor of the transcription protein nuclear factor κB (NF-κB). We examined mRNA and protein levels of vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1) by real-time RT-PCR and Western blotting, respectively. Retinal levels of CaMKII and NF-κB were examined by Western blotting. Vascular leakage was evaluated using Evans blue. Results: Curcumin and KN93 significantly inhibited the activation of CaMKII/NF-κB signaling induced by diabetes or elevated glucose, and subsequently decreased the expression of VEGF, iNOS and ICAM-1. These changes were associated with a decrease of diabetes-induced retinal vascular leakage. Conclusion: Curcumin protects the diabetic rat retina against early retinal vascular damage, by inhibition of CaMKII activity. Curcumin is currently used to treat a number of clinical conditions, and may prove beneficial for the management of diabetic retinopathy.