Involvement Of Pkc In Renal Hemodynamics

The effects of PKC-P isoform inhibitor, LY333531, on renal hemodynamics were examined first. These functional parameters included glomerular filtration rates (GFR) and urinary albumin excretion rates (UAE). Treatment with LY333531 orally at the onset of diabetes normalized GFR and glomerular PKC activity in a dose-dependent manner [17]. Intervention treatment with LY333531 also ameliorated the increase in urinary albumin excretion rate in diabetic rats 12 weeks after the onset of diabetes [17], suggesting that PKC-P activation may cause the early hemodynamic and histological abnormalities which have been implicated to be responsible for glomerular injury leading to the progression of diabetic nephropathy. Unlike PKC-P inhibitor, vitamin E treatment in diabetic rats reduced renal DAG levels, normalized PCK-P activation and glomerular filtration rates [32].

Treatment with high-dose of vitamin E in type 1 diabetic patients, with <10 years duration of disease and no microalbuminuria, significantly normalized renal hyperfiltration. Diabetic patients with the highest creatinine clearances and poorest glycemic control showed the most marked normalization in response to vitamin E treatment [33].

One possible mechanism to explain renal hyperfiltration in poorly controlled diabetes is the increase in vasodilatory prostanoids such as prostaglandin E2 (PGE2) which have been noted in the kidney of diabetic patients and animals with glomerular hyperfiltration [36, 37]. We have reported that the possible overproduction of glomerular PGE2 in the glomeruli of diabetic rats could be due to an enhanced synthesis of arachidonic acid via the activation of cytosolic phospholipase A2 (cPLA2) by PKC since specific inhibitor of PKC-P isoform was able to decrease PGE2 and arachidonic acid release by hyperglycemia [30]. Haneda et al. have found that the increase in mitogen-activated protein kinase (MAPK) activity, which was dependent on diabetes-induced activation of PKC pathway, was able to enhance cPLA2 activity, resulting in increase in arachidonic acid release in glomerular mesangial cells exposed to elevated glucose levels [38]. Williams et al. have also reported similar findings showing that PKC activation by glucose increased PGE2 production through cPLA2 and it was normalized in the presence of general PKC inhibitors such as H-7 or staurosporine in glomerular mesangial cells [6].

These results strongly support that diabetes-induced hyperfiltration could be due to an overproduction of vasodilatory prostanoids through the activation of cPLA2 which was due to the activation of PKC-MAPK pathway. In addition, Igarashi et al. identified p38 MAP kinase as a possible intermediate target, in vascular cells, which can be activated by high glucose levels and diabetes [39]. Its activation is mediated by either PKC-dependent or -independent pathways, with the latter induced significantly by levels of hyperglycemia not usually observed clinically. At moderate and commonly encountered levels of hyperglycemia, p38 MAP kinase was activated by PKC-P isoform-dependent processes [39].

Another important biochemical change induced by DAG-PKC activation is the inhibition of Na+-K+ ATPase, an integral component of the sodium pump, which is involved in the maintenance of cellular integrity and functions such as contractility, growth, and differentiation [40]. Its inhibition has been well established in the vascular and neural tissues of diabetic patients and diabetic experimental animals [6]. However, the mechanisms by which hyperglycemia can inhibit Na+-K+ ATPase is still unclear especially regarding the role of PKC. We have found that PKC activation induced by diabetes or hyperglycemia can lead to the inhibition of Na+-K+ ATPase. PKC-P inhibitor prevented the decrease of Na+-K+ATPase induced by hyperglycemia, suggesting the importance of PKC-P activation in the development of mesangial or glomerular dysfunctions which are due to the inhibition of Na+-K+ ATPase activity in diabetes [30].

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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