Oral Targeting of Protein Kinase C Receptor: Promising Route for Diabetic Retinopathy?

Abstract

In patients with diabetes, hyperglycemia is known to promote high levels of diacylglycerol which activates protein kinase C (PKC) in the vascular tissues and leads to the production of vascular endothelial growth factor (VEGF) in the retina. PKC activation and increased concentration of VEGF are likely to play a key role in diabetic microvascular complications, particularly change in vascular permeability, inflammation, fluid leakage and ischemia in the retina. PKC comprises a super family of isoenzymes that is activated in response to various stimuli. The PKC family consists of 12 isomers that possess distinct differences in structure, substrate requirement, expression and localization. PKC isomer selective inhibitors and VEGF trap are likely to be new therapeutics, which can delay the onset or stop the progression of diabetic vascular disease. A new promising therapy for diabetic retinopathy is undergoing Phase III trials, in which they proposed to target PKC βII isomer using Ruboxistaurin by oral administration. Besides retina, PKC βII isomer is found in higher concentration in brain, spleen, etc. So, oral targeting may be a questionable approach since generalized inhibitors may prove toxic in the treatment of diabetic retinopathy and ocular delivery may be a better alternative approach.

Recent advances in understanding the biochemical and molecular mechanism of diabetic retinopathy

“…PKC activation also contributes to ROS production and oxidative stress by increasing the activity of NADPH oxidases [12]. Other effects induced by PKC activation include inhibition of endothelial nitric oxide synthase expression in endothelia cells [13], increased expression of vascular endothelial growth factor in vascular smooth muscle cells, and decreased nitric oxide production in smooth muscle cells [14,15]. Activation of PKC by hyperglycemia also induces expression of transforming growth factor b, which is suggested to be the major mediator of fibrosis in the diseases associated with sclerosis, such as diabetic nephropathy [16].…”

Antioxidant Effects and Mechanisms of Medicinal Plants and Their Bioactive Compounds for the Prevention and Treatment of Type 2 Diabetes: An Updated Review

“…It was revealed that its activation is enhanced by increased glucose levels in diabetic animals and vascular cells [44,45]. In recent times, high glucose levels induce the activation of PKC and the increase in the levels of diacylglycerol (DAG) in a number of tissues (retina, aorta, heart, and renal glomeruli) are involved in diabetic vascular complications using diabetic animal models and patients [46][47][48]. Also, a large amount of clinical and animal experimental models implicated elevated glucose levels to be the direct activator of the polyol pathway, and it is also linked with the excessive generation of reactive oxygen species (ROS) by the activity of mitochondria, PKC, and NADPH oxidase [49,50].…”

Molecular mechanisms of diabetic retinopathy: Potential therapeutic targets

“…Protein kinase C family, including eight isozymes, is ubiquitously expressed in many cell types and has distinct signaling roles in both health and disease including DR (reviewed in). 98 In particular, two PKC isozymes, PKCd and PKCβ, have been implicated in the pathogenesis of diabetes. PKCd plays a role in diabetes by influencing beta-islet cell function and insulin resistance, it is PKCβ that plays an important role in diabetic microvascular complications.…”