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      Effects of Blocking the Renin-Angiotensin System on Expression and Translocation of Protein Kinase C Isoforms in the Kidney of Diabetic Rats

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          Background: High glucose and angiotensin II (Ang II) can activate protein kinase C (PKC) in diabetes mellitus. However, it is not clear which isoform of PKC is activated by glucose or Ang II. Our study focused on the effects of angiotensin blockade, using the angiotensin-converting enzyme inhibitor fosinopril, the Ang II receptor blocker irbesartan and their combination, on the expression and translocation of PKC isoforms α and βII in the renal cortex and medulla in diabetes. Methods: Hyperglycemia was induced with streptozotocin and diabetic rats were randomized to 4 groups: diabetic control, irbesartan group (40 mg/kg daily), fosinopril group (40 mg/kg daily) and combination group (irbesartan plus fosinopril, 20 mg/kg daily, respectively); age-matched normal rats served as normal control. After 4 weeks, expression and translocation of PKC-α and -βII in the renal cortex and medulla were assessed by immunohistochemistry and Western immunoblotting. Results: The expression of PKC-α in the membrane and cytosol fractions from the renal cortex was significantly higher in diabetic rats (276.83 ± 32.44% in membrane, 149.04 ± 23.42% in cytosol) than that in normal ones. The expression of PKC-βII in the renal cortex of diabetic rats decreased significantly in the membrane (50.00 ± 11.68%, p < 0.05) and remained unchanged in the cytosol (94.51 ± 11.69%, p > 0.05) compared with normal controls. Treatment with irbesartan, fosinopril and their combination partially corrected the abnormalities mentioned above. For the expression of PKC-α and -βII in the medulla, no difference was detected among the 5 groups. Conclusion: The renin-angiotensin system was implicated in the pathogenesis of diabetic nephropathy by regulating the activation of PKC isoforms.

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          Most cited references 30

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          The c-Fos protein interacts with c-Jun/AP-1 to stimulate transcription of AP-1 responsive genes.

          Cell lines stably transfected with metal inducible, MT-fos chimeric genes were used to study the ability of the c-fos gene product, Fos, to act as a transcriptional trans-activator. In 3T3MTfos cells, induction of Fos expression led to specific trans-activation of an AP-1 responsive reporter gene. Induction of Fos expression in F9MTfos cells, however, did not lead to trans-activation. Since, unlike NIH3T3 cells, F9 cells do not contain detectable levels of AP-1, we examined whether a c-Jun/AP-1 expression vector can restore the trans-activating effect of Fos in F9MTfos cells. Transfection with a functional c-Jun/AP-1 vector restored the specific trans-activating effect of Fos on AP-1 responsive constructs. When incubated with nondenatured cell extracts, anti-cFos antisera precipitated a protein complex composed of Fos and several Fos associated proteins (FAP). One of these, FAP p39, is structurally identical to c-Jun/AP-1. These results suggest that Fos is a trans-acting factor that is capable of stimulating gene expression not by direct binding to DNA but by interaction with the sequence-specific transcription factor AP-1. Therefore recognition of specific cis-elements by AP-1 is a prerequisite for Fos-mediated stimulation of gene expression.
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            Hyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator.

             S. Sharma,  F Ziyadeh (1995)
            Renal cells are a rich source of transforming growth factor (TGF)-beta, and they serve as targets for its actions. Our hypothesis that activation of the TGF-beta system in the kidney is implicated in the development of diabetic renal disease stems from the close similarity of actions of TGF-beta and high ambient glucose on renal cell growth and extracellular matrix metabolism. Proximal tubule cells and glomerular mesangial cells cultured in high glucose concentration express increased TGF-beta 1 mRNA and protein levels, and treatment with anti-TGF-beta antibodies results in prevention of the effects of high glucose to induce cellular hypertrophy and stimulate collagen biosynthesis. Several in vivo studies by different groups of investigators have reported overexpression of TGF-beta in the glomeruli in human and experimental diabetes. We have also observed that the development of renal hypertrophy in the insulin-dependent diabetic BB rat and NOD mouse is associated with increased expression of TGF-beta 1 in the kidney and that short-term administration of antibodies capable of neutralizing the activity of TGF-beta in the streptozotocin mouse model of diabetes results in attenuation of whole kidney and glomerular hypertrophy and overexpression of mRNAs encoding matrix components. Together, these findings are consistent with the hypothesis that the diabetic state stimulates TGF-beta expression in the kidney and that in turn this growth factor may mediate, in an autocrine/paracrine manner, some of the principal early manifestations of diabetic renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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              Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC beta Inhibitor


                Author and article information

                Nephron Exp Nephrol
                Cardiorenal Medicine
                S. Karger AG
                October 2006
                14 July 2006
                : 104
                : 3
                : e103-e111
                aDepartment of Nephrology, First Affiliated Hospital of Nanjing Medical University, Jiangsu, and bDepartment of Nephrology, Huashan Hospital, Fudan University, Shanghai, China
                94549 Nephron Exp Nephrol 2006;104:e103–e111
                © 2006 S. Karger AG, Basel

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                Figures: 6, Tables: 2, References: 47, Pages: 1
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