Protein kinase C activation and the development of diabetic complications.

Abstract

Recent studies have identified that the activation of protein kinase C (PKC) and increased diacylglycerol (DAG) levels initiated by hyperglycemia are associated with many vascular abnormalities in retinal, renal, and cardiovascular tissues. Among the various PKC isoforms, the beta- and delta-isoforms appear to be activated preferentially in the vasculatures of diabetic animals, although other PKC isoforms are also increased in the renal glomeruli and retina. The glucose-induced activation of PKC has been shown to increase the production of extracellular matrix and cytokines; to enhance contractility, permeability, and vascular cell proliferation; to induce the activation of cytosolic phospholipase A2; and to inhibit Na+-K+-ATPase. The synthesis and characterization of a specific inhibitor for PKC-beta isoforms have confirmed the role of PKC activation in mediating hyperglycemic effects on vascular cells, as described above, and provide in vivo evidence that PKC activation could be responsible for abnormal retinal and renal hemodynamics in diabetic animals. Transgenic mice overexpressing PKC-beta isoform in the myocardium developed cardiac hypertrophy and failure, further supporting the hypothesis that PKC-beta isoform activation can cause vascular dysfunctions. Interestingly, hyperglycemia-induced oxidative stress may also mediate the adverse effects of PKC-beta isoforms by the activation of the DAG-PKC pathway, since treatment with D-alpha-tocopherol was able to prevent many glucose-induced vascular dysfunctions and inhibit DAG-PKC activation. Clinical studies are now in progress to determine whether PKC-beta inhibition can prevent diabetic complications.

In situ protein Kinase C activity is increased in cultured fibroblasts from Type 1 diabetic patients with nephropathy

“…Although amongst the many isoforms of PKC, PKCβII isoform has been reported to be predominantly activated by hyperglycaemia in all vascular tissues [11], we did not detect any specific immunoreactivity for PKCβII in fibroblasts from normal and diabetic subjects, as reported by others [27]. It is known that the specific PKC isoform activated by hyperglycaemia varies across tissues and species [28].Thus, involvement of PKC in the vascular dysfunction of diabetes might depend on the bed studied.…”

“…PKC activation regulates a variety of cellular functions including permeability, contractility, cellular proliferation, basement membrane biosynthesis and responsiveness to cytokines and hormones [10,11]. There is increasing evidence that increased extracellular glucose concentrations can activate several isoforms of protein kinase C as a consequence of a glucose-driven increase in de novo synthesis of diacylglycerol [10,11].…”

“…PKC activation regulates a variety of cellular functions including permeability, contractility, cellular proliferation, basement membrane biosynthesis and responsiveness to cytokines and hormones [10,11]. There is increasing evidence that increased extracellular glucose concentrations can activate several isoforms of protein kinase C as a consequence of a glucose-driven increase in de novo synthesis of diacylglycerol [10,11]. Cultured skin fibroblasts have proven to be a useful tool for investigation of various genetic errors of metabolism and our earlier results suggest that these cells could help to identify intrinsic abnormalities of cell function which might participate in the pathogenesis of diabetic cardiorenal complications [6,7,8,12].…”

Endothelial dysfunction in diabetes

“…Protein kinase C Another glucose-induced alteration in cellular metabolism that may account for endothelial dysfunction is activation of protein kinase C. Hyperglycaemia causes de novo synthesis of diacylglycerol, leading to activation of protein kinase C -preferentially the b-isoform-, a pathway now demonstrated in all vascular tissues involved in diabetic complications (Craven et al, 1995;Koya & King, 1998). The consequences of protein kinase C activation are multiple, since it is involved in a variety of cellular functions (Koya & King, 1998).…”

Medical treatment of diabetic retinopathy

“…PKC beta isoform activation has been shown to inhibit the sodium potassium ATPase pump, and is known to upregulate genes coding for basement membrane proteins such as fibronectin and type IV collagen (see Figure 9). 57,58 Early inhibitors of PKC (H7 and Staurosporine) blocked all PKC isoforms (A, B, and C) and consequently had limited clinical usefulness. Vitamin E is known to decrease glucose-induced PKC activation by promoting the clearance of DAG via an effect on DAG kinase but the effect is not strong.…”