Effect of Chronic Treatment with Vitamin E on Endothelial Dysfunction in a Type I in Vivo Diabetes Mellitus Model and in Vitro

Dhein, Stefan; Kabat, Armin; Olbrich, Antje; Rösen, P.; Schröder, H.; Mohr, Friedrich W.

doi:10.1124/jpet.102.045740

Cited by 26 publications

(20 citation statements)

References 60 publications

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“…The animals did not receive an antidiabetic treatment. Diabetic rats had stable, moderate hyperglycemia throughout the 2 months (mean blood glucose concentrations, Ͼ400 mg/dl) (Dhein et al, 2003). After 2 months, the experiment was terminated.…”

Section: Methodsmentioning

confidence: 99%

RSK4 and PAK5 Are Novel Candidate Genes in Diabetic Rat Kidney and Brain

Niehof¹,

Borlak²

2004

Mol Pharmacol

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The orphan hepatic nuclear factor (HNF) HNF4␣ is of pivotal importance for liver development and hepatocellular differentiation and plays an essential role in a regulatory circuitry to control a wide range of metabolic processes. It also targets genes in other organs, including pancreas, kidney, intestine, and colon; promotes expression of an epithelial phenotype; triggers de novo formation of functional tight junctions; and contributes to epithelial cell polarity. In particular, HNF4␣ dysfunction leads to metabolic disorders, including diabetes. We used the chromatin immunoprecipitation (ChIP) cloning procedure and a bioinformatic approach to search for candidate genes associated with impaired liver, pancreas, and kidney function. We identified two novel targets regulated by HNF4␣, which participate in the control, at least in part, in cell-cycle regulation and are members of the mitogenactivated kinase pathway. In multiple ChIP assays, ribosomal S6 kinase 4 (RSK4) and p21-activated kinase 5 (PAK5) were confirmed, and in vitro binding of HNF4␣ was evidenced by electrophoretic mobility shift assays (EMSA) using oligonucleotides, which harbor novel binding sites. We also used EMSA to probe for binding sites in promoters of HNF1␣, apolipoprotein B, ␣1-antitrypsin, and angiotensinogen. We further studied RSK4 and PAK5 kinase expression in streptozotocin-induced diabetic rat kidney and brain and observed significant repression of HNF4␣, RSK4, and PAK5 as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. RSK4 and PAK5 may provide a molecular rationale for late-stage complications in disease, and further studies are warranted to explore these targets for the treatment of diabetic nephro-and neuropathy, frequently seen in patients with HNF4␣ dysfunction.

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Section: Methodsmentioning

confidence: 99%

RSK4 and PAK5 Are Novel Candidate Genes in Diabetic Rat Kidney and Brain

Niehof¹,

Borlak²

2004

Mol Pharmacol

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“…The animals did not receive an antidiabetic treatment. Diabetic rats had stable moderate hyperglycemia throughout the 2 months (mean blood glucose concentrations Ͼ400 mg/dl) (19). After 2 months the experiment was terminated.…”

Section: Methodsmentioning

confidence: 99%

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Niehof

Borlak

2008

Diabetes

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OBJECTIVE-The nuclear receptor hepatic nuclear factor 4␣ (HNF4␣) is a master regulatory protein and an essential player in the control of a wide range of metabolic processes. Dysfunction of HNF4␣ is associated with metabolic disorders including diabetes. We were particularly interested in investigating molecular causes associated with diabetic nephropathy.RESEARCH DESIGN AND METHODS-Novel disease candidate genes were identified by the chromatin immunoprecipitation-cloning assay and by sequencing of immunoprecipitated DNA. Expression of candidate genes was analyzed in kidney and liver of Zucker diabetic fatty (ZDF) and of streptozotocin (STZ)-administered rats and after siRNA-mediated silencing of HNF4␣.RESULTS-We identified the calcium-permeable nonselective transient receptor potential cation channel, subfamily C, member 1 (TRPC1) as a novel HNF4␣ gene target. Strikingly, TRPC1 is localized on human chromosome 3q22-24, i.e., a region considered to be a hotspot for diabetic nephropathy. We observed a significant reduction of TRPC1 gene expression in kidney and liver of diabetic ZDF and of STZ-administered rats as a result of HNF4␣ dysfunction. We found HNF4␣ and TRPC1 protein expression to be repressed in kidneys of diabetic patients diagnosed with nodular glomerulosceloris as evidenced by immunohistochemistry. Finally, siRNA-mediated functional knock down of HNF4␣ repressed TRPC1 gene expression in cell culture experiments.CONCLUSIONS-Taken collectively, results obtained from animal studies could be translated to human diabetic nephropathy; there is evidence for a common regulation of HNF4␣ and TRPC1 in human and rat kidney pathologies. We propose dysregulation of HNF4␣ and TRPC1 as a possible molecular rationale in diabetic nephropathy.

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“…In isolated mesenteric beds of Wistar rats with diabetes for 6 months, a reduction in endothelium-dependent relaxation was found (22). In addition, cultures of porcine aortic endothelial cells (PAECs) submitted to high-glucose concentrations showed an endothelial dysfunction mediated by hyperglycemia, which was revealed by reduced endothelial NO production or release (22)(23), as well as severe changes in endothelial cell structure (24). More recently, several studies suggested plasma glucose fluctuations and glucose peaks, such as those occurring in the postabsorptive state, to provide a strong contribution to the development of endothelial dysfunction (25)(26)(27).…”

Section: Cardiovascular Datamentioning

confidence: 99%

Repaglinide Administration Improves Brachial Reactivity in Type 2 Diabetic Patients

et al. 2005

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OBJECTIVE -Several studies have demonstrated that endothelial dysfunction plays a central role in diabetic mortality and that the prooxidative effect of postprandial hyperglycemia may actively contribute to atherogenesis. Thus, we investigated the possible effect of short-acting (repaglinide) and long-acting (glibenclamide) insulin secretagogues on endothelial function in type 2 diabetic patients.RESEARCH DESIGN AND METHODS -Sixteen type 2 diabetic patients undergoing diet treatment and with poor glucose control volunteered for the study. The study was designed as a 4-month, randomized, cross-over, parallel-group trial of repaglinide (1 mg twice a day) versus glibenclamide (5 mg twice a day). All patients underwent the following investigations: 1) anthropometrics determinations, 2) blood sampling for routine laboratory analyses and for assessment of oxidative stress indexes, and 3) a brachial reactivity test to evaluate the endothelial function through the study of arterial diameter and flow changes with and without intraarterial infusion of N G -monomethyl-L-arginine, an inhibitor of nitric oxide synthase and tetraethylammonium chloride (TEA), a Ca 2ϩ -activated K ϩ (K Ca ) channel blocker. All patients were randomly assigned to receive repaglinide or glibenclamide for a period of 4 weeks. RESULTS -Repaglinide administration was associated with a significant reduction in 2-h plasma glucose levels (P Ͻ 0.001) and in plasma thiobarbituric acid-reactive substances (TBARS) concentrations (P Ͻ 0.001) and with a significant increase in plasma antioxidant power, assessed as Trolox equivalent antioxidant capacity (TEAC) (P Ͻ 0.001), effects not observed after glibenclamide administration. With regard to brachial reactivity parameters, repaglinide but not glibenclamide was associated with a significant improvement in brachial reactivity parameters (P Ͻ 0.003 for all parameters). In contrast, intra-arterial infusion of L-NMMA and TEA reduced the beneficial effect of repaglinide.CONCLUSIONS -Repaglinide administration, through good control of postprandial glucose levels, improves brachial reactivity and declines oxidative stress indexes. Diabetes Care 28:366 -371, 2005R ecent studies have suggested that plasma glucose fluctuations, such as those occurring in the absorptive state, may not only be an important determinant of overall glucose control and risk of diabetes complications, but they may also exert an independent negative effect on long-term outcomes of diabetes (1-4). In fact, acute elevations of plasma glucose concentrations trigger an array of tissue responses that may contribute to the development of vascular complications (5). Whether antihyperglycemic agents with different pharmacokinetic profiles may have diverse effects on endothelial function is still unknown. In fact, one cannot rule out that drugs having different pharmacokinetic profiles, through a reduced or a more profound effect on postprandial glucose levels, could exert a diverse impact on oxidative stress at the endothelial level.Repaglinide and g...

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Effect of Chronic Treatment with Vitamin E on Endothelial Dysfunction in a Type I in Vivo Diabetes Mellitus Model and in Vitro

Cited by 26 publications

References 60 publications

RSK4 and PAK5 Are Novel Candidate Genes in Diabetic Rat Kidney and Brain

RSK4 and PAK5 Are Novel Candidate Genes in Diabetic Rat Kidney and Brain

HNF4α and the Ca-Channel TRPC1 Are Novel Disease Candidate Genes in Diabetic Nephropathy

Repaglinide Administration Improves Brachial Reactivity in Type 2 Diabetic Patients

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