Effect of Protein Kinase C Inhibition on Renal Hemodynamic Function and Urinary Biomarkers in Humans With Type 1 Diabetes: A Pilot Study (original) (raw)
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Canadian Journal of Physiology and Pharmacology, 2012
The protein kinase Cb (PKCb) system has been implicated in the deleterious vascular responses to hyperglycemia and angiotensin II (Ang II) in experimental models of diabetes (DM). Whether these interactions are important in humans is unknown. Flow-mediated vasodilatation (FMD) was measured during clamped euglycemia and hyperglycemia, before and after randomization to PKCb inhibition (ruboxistaurin; RBX, 32 mg daily, n = 13) or a placebo (n = 7) for 8 weeks in renin-angiotensin system (RAS) blockade-treated subjects with type 1 DM. Blood pressure responses to infused Ang II were measured before and after randomization to RBX or a placebo. The RBX and placebo groups displayed similar clinical characteristics. Before RBX, FMD declined in response to hyperglycemia (6.8% ± 2.8% to 4.9% ± 1.8%). This effect was reversed after treatment with RBX (5.6% ± 3.1% to 6.0% ± 1.6% (within-group change, p = 0.009 (ANOVA)). No changes were observed in the placebo group. Infused Ang II was associated with hypertensive responses in the RBX and placebo groups (p < 0.05 (ANOVA)), and RBX did not influence this effect. In conclusion, RBX blunted the effect of hyperglycemia on FMD, suggesting that PKCb may modulate endothelial function in type 1 DM. The lack of effect on Ang II responses suggests that PKCb inhibition may act through non-RAS pathways in humans with DM.
Relationship Between Protein Kinase C and Diabetic Nephropathy Patients in Al Anbar City
Pakistan Journal of Medical and Health Sciences
Background : Diabetic syndrome is characterized by increase blood sugar and resistance to insulin. It is linked to macrovascular and microvascular complications such as nephropathy, neuropathy, and retinopathy . the aim of this study to investigate the relationship protein kinase C and diabetic nephropathy. Material and Methods: The study was include 84 samples , 36 of them with type 2 diabetes, 23 of them with diabetic nephropathy, and 25 healthy controls population , all of whom were over the age of 40. ELISA was used to calculate the protein kinase C level, fasting serum sugar , Glycated Hemoglobin ,Urea, Creatinine, Total protein, Albumin, and globulin were all found. Body mass index was also calculated. Result : the study result shown approximately same level between healthy and patients groups and this also associated with increase in fasting serum sugar , Glycated Hemoglobin , Urea , Creatinine and body mass index in patients group compared to Healthy controls group. Conclusi...
Diabetologia, 2003
Aims/hypothesis To verify whether individual susceptibility to diabetic nephropathy resides in an intrinsic difference in Protein Kinase C (PKC) activity. Methods We compared the effect of different glucose concentrations on PKC activity, PKC isoform expression and diacylglycerol (DAG) content in cultured fibroblasts from 14 Type 1 diabetic patients who developed nephropathy with those in cells from 14 patients without nephropathy. We recruited 14 normal subjects as control patients. Forearm skin fibroblasts were cultured in either normal (5 mmol/l) or high (20 mmol/l) glucose concentrations. Results In normal glucose, in situ PKC activity was higher in Type 1 patients with nephropathy (10.1±1.4 pmol/min/mg protein; p<0.01) than in those without (6.8±0.8) and the normal control subjects (6.3±0.5). This difference was due to increased concentrations of PKCα isoform in the membrane fraction of fibroblasts from patients with nephropathy. DAG content was also higher in cells from Type 1 patients with nephropathy. Incubation in high glucose concentration caused a further increase in PKC activity and DAG content in quiescent fibroblasts from patients with diabetic nephropathy, with no significant changes in cells from diabetic patients without nephropathy and normal control subjects. Conclusion/interpretation Differences in PKC activation could contribute to the individual susceptibility to renal damage in Type 1 diabetic patients.
Diabetes, 2007
The protein kinase C (PKC)-β isoform has been implicated to play a pivotal role in the development of diabetic kidney disease. We tested this hypothesis by inducing diabetic nephropathy in PKC-β–deficient (PKC-β−/−) mice. We studied nondiabetic and streptozotocin-induced diabetic PKC-β−/− mice compared with appropriate 129/SV wild-type mice. After 8 weeks of diabetes, the high-glucose–induced renal and glomerular hypertrophy, as well as the increased expression of extracellular matrix proteins such as collagen and fibronectin, was reduced in PKC-β−/− mice. Furthermore, the high-glucose–induced expression of the profibrotic cytokine transforming growth factor (TGF)-β1 and connective tissue growth factor were significantly diminished in the diabetic PKC-β−/− mice compared with diabetic wild-type mice, suggesting a role of the PKC-β isoform in the regulation of renal hypertrophy. Notably, increased urinary albumin-to-creatinine ratio persisted in the diabetic PKC-β−/− mice. The loss of...
Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways
Journal of Pharmacy and Pharmacology, 2016
ObjectiveTo investigate whether ruboxistaurin (a selective PKC-β inhibitor) mediates renoprotective effect via interference with TGF-β1/Smad-GRAP cross-signalling.MethodDiabetes was induced in rats by a single intraperitoneal injection of streptozotocin (55 mg/kg). Then, the diabetic rats were treated with ruboxistaurin (10 mg/kg, p.o) for 6 weeks. Valsartan (15 mg/kg, p.o) was used as a positive control. After 6 weeks of treatment, diabetic nephropathy biomarkers were assessed. TGF-β1, Smad2, and Smad3 mRNA and protein levels were detected using qPCR and western blot analysis.Key findingsData showed that serum creatinine, kidney/body weight ratio and urinary albumin excretion significantly increased in diabetic rats. These changes were significantly attenuated by treatment with ruboxistaurin. A significant up-regulation of TGF-β1, Smad2 and Smad3 mRNA expression was observed in diabetic rats, which was alleviated by administration of ruboxistaurin. Furthermore, immunoblotting showe...
Diabetes, 2013
Activation of protein kinase C (PKC) has been implicated in the pathogenesis of diabetic nephropathy with proteinuria and peritubular extracellular matrix production. We have previously shown that the PKC isoforms α and β mediate different cellular effects. PKC-β contributes to hyperglycemia-induced renal matrix production, whereby PKC-α is involved in the development of albuminuria. We further tested this hypothesis by deletion of both isoforms and used a PKC inhibitor. We analyzed the phenotype of nondiabetic and streptozotocin (STZ)-induced diabetic homozygous PKC-α/β double-knockout mice (PKC-α/β−/−). After 8 weeks of diabetes mellitus, the high-glucose–induced renal and glomerular hypertrophy as well as transforming growth factor-β1) and extracellular matrix production were diminished in the PKC-α/β−/− mice compared with wild-type controls. Urinary albumin/creatinine ratio also was significantly reduced, however, it was not completely abolished in diabetic PKC-α/β−/− mice. Trea...
Cardiovascular Drugs and Therapy, 2009
Purpose-Type-2 diabetes mellitus increases risk of atherosclerotic cardiovascular disease. However, the mechanisms linking hyperglycemia and atherosclerosis remain poorly understood. One proposed mechanism involves endothelial dysfunction via activation of protein kinase C beta (PKC beta). Prior studies demonstrate beneficial effects of PKC beta inhibition on microvascular parameters, but, to date, no study has examined the effect on macrovascular atherosclerotic readouts.