Protein kinase C in diabetic nephropathy

Craven, Patricia A.; Studer, Rebecca K.; Negrete, Hilmer; DeRubertis, Frederick R.

doi:10.1016/1056-8727(95)80012-4

Cited by 45 publications

(24 citation statements)

References 43 publications

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“…The observation that stretch-induced VPF is mediated via PKC activation has particular relevance for diabetes because PKC is also activated by high glucose concentration (52). Moreover, an oral inhibitor of the ␤ 2 isoform of PKC significantly prevents the development of proteinuria in the experimental diabetic rat (53).…”

Section: Discussionmentioning

confidence: 99%

Mechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction

Gruden

Thomas

Burt

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

114

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Hemodynamic abnormalities have been implicated in the pathogenesis of the increased glomerular permeability to protein of diabetic and other glomerulopathies. Vascular permeability factor (VPF) is one of the most powerful promoters of vascular permeability. We studied the effect of stretch on VPF production by human mesangial cells and the intracellular signaling pathways involved. The application of mechanical stretch (elongation 10%) for 6 h induced a 2.4-fold increase over control in the VPF mRNA level (P < 0.05). There was a corresponding 3-fold increase in VPF protein level by 12 h (P < 0.001), returning to the baseline by 24 h. Stretch-induced VPF secretion was partially prevented both by the protein kinase C (PKC) inhibitor H7 (50 M: 72% inhibition, P < 0.05) and by pretreatment with phorbol ester (phorbol-12-myristate-13 acetate 10 ؊7 M: 77% inhibition, P < 0.05). A variety of protein tyrosine kinase (PTK) inhibitors, genistein (20 g͞ml), herbimycin A (3.4 M), and a specific pp60 src peptide inhibitor (21 M) also significantly reduced, but did not entirely prevent, stretch-induced VPF protein secretion (respectively 63%, 80%, and 75% inhibition; P < 0.05 for all). The combination of both PKC and PTK inhibition completely abolished the VPF response to mechanical stretch (100% inhibition, P < 0.05). Stretch induces VPF gene expression and protein secretion in human mesangial cells via PKC-and PTK-dependent mechanisms.

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Section: Discussionmentioning

confidence: 99%

Mechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction

Gruden

Thomas

Burt

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

114

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“…Advanced glycation end products could induce radical formation directly as well as indirectly by activating their cellular receptors (RAGE) [30,31,32]. In addition, hyperglycaemia leads to activation of protein kinase C [33,34], which has also been shown to result in the induction of oxygen radical stress [35]. Activation of the polyol pathway by hyperglycaemia and glucoseauto oxidation are able to induce oxygen radical stress [36,37].…”

Section: Discussionmentioning

confidence: 99%

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

et al. 2002

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Aims/hypothesis. Patients with diabetes are characterised by endothelial dysfunction and cardiovascular mortality. In particular endothelium-derived nitric oxide has emerged as a first line mechanism against atherosclerosis. Hyperglycaemia causes oxygen radical stress but has also been associated with endothelial nitric oxide synthase uncoupling, both lead to decreased nitric oxide-availability. We recently showed that folate reverses eNOS uncoupling in vitro. Therefore we hypothesise that folate improves endothelial function in Type II (non-insulin-dependent) diabetes mellitus in vivo. Methods. Using forearm plethysmography, we evaluated the effect of local, intra-arterial administration of 5-methyltetrahydrofolate (5-MTHF, the active form of folic acid, 1 µg/100 ml FAV/min) on forearm blood flow in 23 patients with Type II diabetes and 21 control subjects, matched for age, sex, blood pressure, body mass index, weight and smoking habits. Serotonin as a stimulator of nitric oxide-dependent vasodilation and sodium nitroprusside as a stimulator of endothelium-independent vasodilation were infused. Results. Serotonin-induced vasodilation was blunted (53±30 vs 102±66 M/C%, p<0.005) and nitroprussideinduced vasodilation was mildly reduced (275±146 vs 391±203 M/C%, p<0.05) in patients with Type II diabetes compared to control subjects. 5-MTHF improved nitric oxide-mediated vasodilation (from 53±30 to 88±59 M/C%, p<0.05) in patients with Type II diabetes mellitus. As expected, 5-MTHF had no effect on forearm blood flow in control subjects. Conclusion/interpretation. These data imply that folate can be used to improve nitric oxide status and to restore endothelial dysfunction in patients with Type II diabetes. Our results provide a strong rationale for the initiation of studies that investigate whether supplementation with folic acid prevents future cardiovascular events in this patient group. [Diabetologia (2002[Diabetologia ( ) 45:1004[Diabetologia ( -1010

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“…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).…”

Section: Aetiology Of Endothelial Dysfunction In Diabetesmentioning

confidence: 99%

Endothelial dysfunction in diabetes

Vriese

Verbeuren

Voorde

et al. 2000

British J Pharmacology

1,015

769

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Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. The endothelium controls the tone of the underlying vascular smooth muscle through the production of vasodilator mediators. The endothelium-derived relaxing factors (EDRF) comprise nitric oxide (NO), prostacyclin, and a still elusive endothelium-derived hyperpolarizing factor (EDHF). Impaired endothelium-dependent vasodilation has been demonstrated in various vascular beds of di erent animal models of diabetes and in humans with type 1 and 2 diabetes. Several mechanisms of endothelial dysfunction have been reported, including impaired signal transduction or substrate availibility, impaired release of EDRF, increased destruction of EDRF, enhanced release of endothelium-derived constricting factors and decreased sensitivity of the vascular smooth muscle to EDRF. The principal mediators of hyperglycaemia-induced endothelial dysfunction may be activation of protein kinase C, increased activity of the polyol pathway, non-enzymatic glycation and oxidative stress. Correction of these pathways, as well as administration of ACE inhibitors and folate, has been shown to improve endothelium-dependent vasodilation in diabetes. Since the mechanisms of endothelial dysfunction appear to di er according to the diabetic model and the vascular bed under study, it is important to select clinically relevant models for future research of endothelial dysfunction.

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Protein kinase C in diabetic nephropathy

Cited by 45 publications

References 43 publications

Mechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction

Mechanical stretch induces vascular permeability factor in human mesangial cells: Mechanisms of signal transduction

Impaired NO-dependent vasodilation in patients with Type II (non-insulin-dependent) diabetes mellitus is restored by acute administration of folate

Endothelial dysfunction in diabetes

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