The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy

Abstract

Diabetic retinopathy is one of the most common complications of diabetes and is a major cause of new blindness in the working-age population of developed countries. While the exact pathogenic basis of this condition remains ill defined, it is clear that hyperglycaemia is a critical factor in its aetiology. Protein kinase C (PKC) activation is one of the sequelae of hyperglycaemia and it is thought to play an important role in the development of diabetic complications. This review questions the currently held dogma that PKC stimulation in diabetes is solely mediated through the overproduction of palmitate and oleate enriched diacylglycerols. Blood glucose concentrations are closely tracked by changes in the levels of free fatty acids and these, in addition to oxidative stress, may account for the aberrant activation of PKCs in diabetes. Little is known about why PKCs fail to downregulate in diabetes and efforts should be directed towards acquiring such information. Considerable evidence implicates the PKCbeta isoform in the pathogenesis of diabetic retinopathy, but other isoforms may also be of relevance. In addition to PKCs, it is evident that novel diacyglycerol-activated non-kinase receptors could also play a role in the development of diabetic complications. Therapeutic agents have been developed to inhibit specific PKC isoforms and PKCbeta antagonists are currently undergoing clinical trials to test their toxicity and efficacy in suppressing diabetic complications. The likely impact of these drugs in the treatment of diabetic patients is considered.

Microvascular lesions of diabetic retinopathy: clues towards understanding pathogenesis?

“…37 Accumulation of sorbitol in retinal cells is dependant on the activity of aldose reductase and this may impinge on a range of pathways and contribute to diabetic retinopathy. 38 Also de novo synthesis of diacylglycerol (DAG) leading to the over-activation of several isoforms of protein kinase C (PKC), 39 excessive production of free radicals leading to oxidative stress, 40,41 changes in blood rheology and haemodynamics, 42,43 and over-activation of the renin-angiotensin system 44 contribute significantly to retinopathy as diabetes progresses. Accumulation of advanced glycation end products (AGEs) and activation of receptors for AGEs are also important pathogenic mechanisms with clear links to diabetic retinopathy.…”

“…36,45 With particular links to early changes in retinal blood flow, there has been considerable emphasis placed on the activation of PKC, including several conventional and novel isoforms such as PKCa, -b, -d, and -e. 46 PKC activation in diabetes may also arise through oxidative stress or increased concentrations of free fatty acids. 47 The PKCbII isoform is preferentially activated in diabetic retinopathy and this can be linked to impaired retinal blood flow. 46 Intravitreal injection of a DAG kinase inhibitor (that elevates total retinal DAG levels) or a PKC-activating phorbol ester serves to decrease retinal blood flow in non-diabetic rats.…”

Protein kinase C expression in the rabbit retina after laser photocoagulation

“…PKC has been linked to various normal retinal functions such as regulation of phototransduction, transmitters, and cytoskeletal interactions, as well as to important roles in pathological conditions [23]. The family of PKC enzymes has been the subject of extensive interest in clinically related research recently since the advent of its role in the pathogenesis of diabetic retinopathy [1,4]. PKC is necessary for many of the various effects of vascular endothelial growth factor (VEGF) [20], one of the key mediators of diabetic retinopathy [3].…”

Neuropeptides, Trophic Factors, and Other Substances Providing Morphofunctional and Metabolic Protection in Experimental Models of Diabetic Retinopathy

“…It is not allowed to publish this proof online or in print. This proof copy is the copyright property of the publisher and is confidential until formal publication.and structural abnormalities occurring in DR (Curtis and Scholfield, 2004;Das Evcimen and King, 2007). …”