Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which contributes to oxidative stress in rat kidney cortex

Abstract

The incidence of diabetic nephropathy has been increasing. Studies have shown that oxidative stress (due to increased oxidant production and/or decreased antioxidant activity) is a critical underlying mechanism. The principal intracellular reductant is NADPH whose production is mainly dependent on glucose-6-phosphate dehydrogenase (G6PD) activity. Our work in cultured cells previously showed that high glucose caused activation of protein kinase A (PKA) and subsequent phosphorylation and inhibition of G6PD activity and hence decreased NADPH (Zhang Z, Apse K, Pang J, and Stanton RC. J Biol Chem 275:40042-40047, 2000). The purpose of this study was to determine whether these findings occur in diabetic rats (induced by streptozotocin) compared with control. G6PD activity and accordingly NADPH levels and glutathione levels were significantly decreased in diabetic kidneys compared with control kidneys. Lipid peroxidation was significantly increased, which correlated with decreased G6PD activity (r = 0.48). G6PD expression was significantly reduced, which correlated with decreased G6PD activity (r = 0.72). PKA activity and serine phosphorylation of G6PD were significantly increased and were closely correlated with decreased G6PD activity (r = 0.51 for PKA activity; r = 0.93 for serine phosphorylation of G6PD). Insulin treatment and/or correction of hyperglycemia ameliorated the changes caused by diabetes. In conclusion, chronic hyperglycemia caused inhibition of G6PD activity via decreased expression and increased phosphorylation of G6PD, which therefore led to increased oxidative stress.

Prevention of Alloxan-induced Diabetes by Se-Methylselenocysteine Pretreatment in Rats: The Effect on Antioxidant System in Pancreas

“…The alloxan-diabetic rats evidenced significantly reduced G6PD activity and increased catalase activity. This decrease in G6PD activity in animal diabetic models has also been reported in other studies, and the activation of protein kinase A and subsequent phosphorylation and inhibition of G6PD has been proposed as the mechanism underlying this phenomenon (30). G6PD is the principal source of NADPH, on which the antioxidant system relies heavily.…”

Attenuation of Armanni–Ebstein lesions in a rat model of diabetes by a new anti-fibrotic, anti-inflammatory agent, FT011

“…In skeletal muscle cells, glycogenin mRNA expression was inhibited with increasing concentrations of cAMP [11], suggesting that diabetic nephropathy may therefore be associated with an inhibition of upstream cAMP-related pathways. While this is an attractive hypothesis, it does not agree with other studies that show increased cAMP and activated downstream signalling molecules such as cAMPdependent protein kinase in diabetic animals [12]. Treatment of diabetic animals with our new anti-fibrotic agent FT011 prevented the accumulation of Armanni-Ebstein lesions (Fig.…”

The contribution of hypertension to diabetic nephropathy and retinopathy: the role of inflammation and oxidative stress

“…To this end, it has been shown that the induction of diabetes in rats leads to a reduction in glucose-6-phosphate dehydrogenase (G6PD) and oxidative stress. 117 A reduction in G6PD activity leads to decreased NADPH and makes cells very sensitive to oxidant damage. 118,119 Deficiency in G6PD activity may lead not only to oxidative stress but also to nephropathy, as it has been shown that G6PD knockout mice have increased renal oxidative stress and elevated albuminuria.…”