Reduction of Diabetes-Induced Oxidative Stress, Fibrotic Cytokine Expression, and Renal Dysfunction in Protein Kinase Cβ–Null Mice

Ohshiro, Yuzuru; Ronald, C.; Yasuda, Yutaka; Hiraoka-Yamamoto, Junko; Clermont, Allen C.; Isshiki, Keiji; Yagi, Kunimasa; Arikawa, Emi; Kern, Timothy S.; King, George L.

doi:10.2337/db06-0895

Cited by 173 publications

(158 citation statements)

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“…In keeping with our findings, Hsieh et al reported recently that glucose-induced damage to proximal tubule cells is dependent on PKC-βI [14]. In addition, although there are conflicting results on which isoform(s) is(are) increased in the glomeruli of STZ-diabetic animals, with reports of increased levels of PKC-α [2, 10, 39], -βI [2,39,40], -δ [41] and -ɛ [10,41], PKC-βI seems to be the pathophysiological isoform [40,42]. Indeed, there is strong evidence that diabetes-induced mesangial cell damage occurs as a result of increased glucose uptake by GLUT1, which correlates with increased PKC-βI activation and fibronectin and collagen accumulation [1].…”

Section: Discussionsupporting

confidence: 90%

“…Levels of the extracellular matrix proteins collagen and fibronectin, as well as those of the profibrotic cytokine TGF-β are decreased in PKC-β −/− mice; moreover, a significant reduction in renal hypertrophy and glomerular enlargement is seen when PKC-β −/− mice are made diabetic and compared with wild-type mice [39,43]. Feeding of LY333531 to animals with STZ-induced diabetes has also been shown to prevent the increases in extracellular matrix components like fibronectin and collagen [2] and to reduce albuminuria and structural injury to the glomerulus [40,42,44].…”

Section: Discussionmentioning

confidence: 98%

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GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

et al. 2007

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Aims/hypothesis GLUT2 is the main renal glucose transporter upregulated by hyperglycaemia, when it becomes detectable at the brush border membrane (BBM). Since glucoseinduced protein kinase C (PKC) activation in the kidney is linked to diabetic nephropathy, we investigated the effect of glycaemic status on the protein levels of PKC isoforms α, βI, βII, δ and ɛ in the proximal tubule, as well as the relationship between them and changes in GLUT2 production at the BBM. Methods Plasma glucose concentrations were modulated in rats by treatment with nicotinamide 15 min prior to induction of diabetes with streptozotocin. Levels of GLUT2 protein and PKC isoforms in BBM were measured by western blotting. Additionally, the role of calcium signalling and PKC activation on facilitative glucose transport was examined by measuring glucose uptake in BBM vesicles prepared from proximal tubules that had been incubated either with thapsigargin, which increases cytosolic calcium, or with the PKC activator phorbol 12-myristate,13-acetate (PMA).Results Thapsigargin and PMA enhanced GLUT-mediated glucose uptake, but had no effect on sodium-dependent glucose transport. Diabetes significantly increased the protein levels of GLUT2 and PKC-βI at the BBM. Levels of GLUT2 and PKC-βI correlated positively with plasma glucose concentration. Diabetes had no effect on BBM levels of α, βII, δ or ɛ isoforms of PKC. Conclusions/interpretation Enhanced GLUT2-mediated glucose transport across the proximal tubule BBM during diabetic hyperglycaemia is closely associated with increased PKC-βI. Thus, altered levels of GLUT2 and PKC-βI proteins in the BBM may be important factors in the pathogenic processes underlying diabetic renal injury.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

et al. 2007

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“…Biochemical effects of elevated ROS included inhibition of Na + /glucose co-transport, increased secretion of TGF-beta1 and activation of NF-kappaB signaling [110]. PKC-beta (−/−) diabetic mice were protected against induction of Nox2, Nox4 and glucose-induced renal dysfunction and fibrosis, indicating a role for PKC in Nox expression and renal pathology [109]. Nox4 is a major source of ROS in diabetic nephropathy, based on protection against high glucose-induced ROS generation and fibronectin expression in kidney cells transfected with Nox4 antisense oligonucleotides [111].…”

Section: B Diabetic Nephropathymentioning

confidence: 99%

“…Apocyanin, an inhibitor of Nox2 and probably other Nox enzymes, was used in rat to test the hypothesis that ROS from a Nox underlies the development of diabetic nephropathy. Diabetes mellitus increased excretion of H 2 O 2 , lipid peroxidation and protein [101,109]. Kidneys of rats with diabetes mellitus had increased expression of Nox2, p47 phox and Nox4 [101,109], increased membrane translocation of p47 phox (reflecting Nox2 activation) [101] and increased mesangial matrix [101].…”

Section: B Diabetic Nephropathymentioning

confidence: 99%

“…Diabetes mellitus increased excretion of H 2 O 2 , lipid peroxidation and protein [101,109]. Kidneys of rats with diabetes mellitus had increased expression of Nox2, p47 phox and Nox4 [101,109], increased membrane translocation of p47 phox (reflecting Nox2 activation) [101] and increased mesangial matrix [101]. Apocyanin prevented the increased H 2 O 2 , lipid peroxidation, and protein in diabetic rats, prevented the increased renal expression of Nox2 and membrane translocation of p47 phox , and blocked the mesangial matrix expansion [101].…”

Section: B Diabetic Nephropathymentioning

confidence: 99%

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Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Lambeth¹

2007

Free Radical Biology and Medicine

590

454

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Genetic Variants of the Protein Kinase C-β 1 Gene and Development of End-Stage Renal Disease in Patients With Type 2 Diabetes

Ronald

Tam²,

Wang³

et al. 2010

JAMA

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SIA IS IN THE MIDST OF AN EPIdemic of type 2 diabetes. 1-3 A recent large-scale epidemiology survey estimated that there are 94.2 million adults affected by diabetes in China, with another 148.2 million with prediabetes. 4 Renal failure is an important cause of mortality among patients with type 2 diabetes. 5,6 Asian populations appear to be particularly at risk of diabetic kidney disease (DKD). In the Microalbuminuria Prevalence (MAP) Study, microalbuminuria was present in 40% and macroalbuminuria in 20% of Asian patients with type 2 diabetes and hypertension. 7 Compared with white individuals, Asian patients have higher risk of end-stage renal disease (ESRD). 8,9 Using a prospective survey, 1% to 3% of Chinese patients with type 2 diabetes developed DKD including ESRD annually depending on baseline risk factors. 10,11 The pathogenesis of DKD is complex and involves hemodynamic, inflammatory, Author Affiliations are listed at the end of this article.

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Reduction of Diabetes-Induced Oxidative Stress, Fibrotic Cytokine Expression, and Renal Dysfunction in Protein Kinase Cβ–Null Mice

Cited by 173 publications

References 50 publications

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

GLUT2 protein at the rat proximal tubule brush border membrane correlates with protein kinase C (PKC)-βl and plasma glucose concentration

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

Genetic Variants of the Protein Kinase C-β 1 Gene and Development of End-Stage Renal Disease in Patients With Type 2 Diabetes

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