A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats.

Abstract

Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of diabetic retinopathy and nephropathy. However, the role of PKC in diabetic neuropathy remains unclear. The present study was conducted to compare the effect of PKC inhibition by a PKC-beta-selective inhibitor, LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhibitor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with or without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MNCV), coefficient of variation of R-R interval (CVR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram, PKC activities in membranous and cytosolic fractions of sciatic nerves, and polyol contents in the tail nerves were measured. Untreated diabetic rats demonstrated delayed MNCV, decreased CVR-R, reduced SNBF, and prolonged peak latencies of oscillatory potentials. Treatment with LY as well as NZ prevented all these deficits in diabetic rats. There were no significant differences in PKC activities in membranous or cytosolic fractions of sciatic nerves between normal and diabetic rats. Treatment with neither LY nor NZ altered PKC activities. Nerve myo-inositol depletion in diabetic rats was ameliorated not only by NZ, but also by LY. These observations suggest that inhibition of PKC-beta by LY may have a beneficial effect in preventing the development of diabetic nerve dysfunction, and that this effect may be mediated through its action on the endoneurial micro-vasculature.

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

“…However, the effects of IGF-1 and the expression of TGF-β have been shown to be influenced by PKC activity [36,37]. Interestingly, hyperglycaemia-induced increase in PKC activity can be reduced by aldose reductase inhibitors [38,39], although other studies have reported ineffectiveness of such treatment [40].…”

O papel da proteína quinase C no desenvolvimento das complicações vasculares do diabetes mellitus

“…Como o aumento da atividade da PKC nos vasa nervorum leva à maior resposta contrátil e redução da vasodilatação, foram realizados estudos utilizando inibidores da PKC, os quais demonstraram efeito positivo sobre a condução nervosa, o que se atribuiu à melhora do fluxo sangüíneo aos nervos (42,43).…”

“…Estes inibidores também preveniram a superexpressão de TGF-β, colágeno α1 e fibronectina em glomérulos de ratos diabéticos, eventos que sabidamente estão envolvidos na gênese da nefropatia diabética (55). Ainda no modelo animal de DM, outros autores demonstraram que o LY333551 determinou normalização de fluxo sangüíneo neuronal e velocidade de condução nervosa (43).…”

Regulation of the Ligand Binding Activity of the Human Very Low Density Lipoprotein Receptor by Protein Kinase C-dependent Phosphorylation

“…Ligand precipitation of biotinylated cell surface proteins using RAPSepharose confirmed that wild type and truncated VLDL-R were expressed in similar amounts on the cell surface. (51,52), and inhibition of hyperglycemia-induced PKC-␤II activation ameliorated the microvascular complications of diabetes in animal models (53,54). To determine whether hyperglycemia induced VLDL-R phosphorylation, we incubated human dermal microvascular endothelial cells for 6 h in the following: 1) control media containing 5.5 mM D-glucose, 2) high glucose medium containing 16.5 mM D-glucose, 3) high galactose medium, identical to high glucose medium except for substitution of galactose (16.5 mM) for glucose, and 4) high mannitol medium in which the inert sugar, mannitol (16.5 mM), was substituted for glucose or galactose.…”

“…Culture of microvascular endothelial cells in the presence of high glucose or galactose stimulates the activation of PK-C by inducing de novo synthesis of diacylglycerol (51,64). Treatment of diabetic rats with a specific PK-C ␤II inhibitor inhibits the development of vascular dysfunction that leads to retinal, renal, and neurologic disease (53,54,65).…”