Publications (54) View all
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Article: Deletion of platelet-derived growth factor receptor-β improves diabetic nephropathy in Ca²⁺/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice.
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ABSTRACT: The activation of platelet-derived growth factor receptor-β (PDGFR-β) signalling is increased in the glomeruli and tubules of diabetic animals. In this study, we examined the role of PDGFR-β signalling during the development of diabetic nephropathy. We recently generated pancreatic beta cell-specific Ca(2+)/calmodulin-dependent protein kinase IIα (Thr286Asp) transgenic mice (CaMKIIα mice), which show very high plasma glucose levels up to 55.5 mmol/l and exhibit the features of diabetic nephropathy. These mice were crossed with conditional knockout mice in which Pdgfr-β (also known as Pdgfrb) was deleted postnatally. The effect of the deletion of the Pdgfr-β gene on diabetic nephropathy in CaMKIIα mice was evaluated at 10 and 16 weeks of age. The plasma glucose concentrations and HbA(1c) levels were elevated in the CaMKIIα mice from 4 weeks of age. Variables indicative of diabetic nephropathy, such as an increased urinary albumin/creatinine ratio, kidney weight/body weight ratio and mesangial area/glomerular area ratio, were observed at 16 weeks of age. The postnatal deletion of the Pdgfr-β gene significantly decreased the urinary albumin/creatinine ratio and mesangial area/glomerular area ratio without affecting the plasma glucose concentration. Furthermore, the increased oxidative stress in the kidneys of the CaMKIIα mice as shown by the increased urinary 8-hydroxydeoxyguanosine (8-OHdG) excretion and the increased expression of NAD(P)H oxidase 4 (NOX4), glutathione peroxidase 1 (GPX1) and manganese superoxide dismutase (MnSOD) was decreased by Pdgfr-β gene deletion. The activation of PDGFR-β signalling contributes to the progress of diabetic nephropathy, with an increase in oxidative stress and mesangial expansion in CaMKIIα mice.Diabetologia 08/2011; 54(11):2953-62. · 6.81 Impact Factor -
Article: [Metabolic syndrome].
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ABSTRACT: The metabolic syndrome means the state of glucose intolerance caused by insulin resistance, and develops lipid abnormality and high blood pressure. Recently, life style is changed to excessive energy intake by a high fat diet and physical activity according to the spread of automobiles decline in. Then, the appearance of disease of obesity and the metabolic syndrome increases. In this text, a basic pathogenesis of the metabolic syndrome and the clinical application of PPARgamma agonist to the metabolic syndrome are outlined.Nippon rinsho. Japanese journal of clinical medicine 02/2010; 68(2):299-304. -
Article: Long-term interleukin-1alpha treatment inhibits insulin signaling via IL-6 production and SOCS3 expression in 3T3-L1 adipocytes.
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ABSTRACT: Proinflammatory cytokines are well-known to inhibit insulin signaling to result in insulin resistance. IL-1alpha is also one of the proinflammatory cytokines, but the mechanism of how IL-1alpha induces insulin resistance remains unclear. We have now examined the effects of IL-1alpha on insulin signaling in 3T3-L1 adipocytes. Prolonged IL-1alpha treatment for 12 to 24 hours partially decreased the protein levels as well as the insulin-stimulated tyrosine phosphorylation of IRS-1 and Akt phosphorylation. mRNA for SOCS3, an endogenous inhibitor of insulin signaling, was dramatically augmented 4 hours after IL-1alpha treatment. Concomitantly, the level of IL-6 in the medium and STAT3 phosphorylation were increased by the prolonged IL-1alpha treatment. Addition of anti-IL-6 neutralizing antibody to the medium or overexpression of dominant-negative STAT3 decreased the IL-1alpha-stimulated STAT3 activation and SOCS3 induction, and ameliorated insulin signaling. These results suggest that the IL-1alpha-mediated deterioration of insulin signaling is largely due to the IL-6 production and SOCS3 induction in 3T3-L1 adipocytes.Hormone and Metabolic Research 02/2008; 40(1):8-12. · 2.19 Impact Factor -
Article: Migraine and adiponectin: is there a connection?
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ABSTRACT: Migraine is a common disorder, characterized by recurrent episodes of headache and associated symptoms. The full pathophysiology of migraine is incompletely delineated. Current theories suggest that it is a neurovascular disorder involving cortical depression, neurogenic inflammation and vasodilation. Various neuropeptides and cytokines have been implicated in the pathophysiology of migraine including calcitonin gene-related peptide, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha. There is evidence demonstrating an association between migraine and processes associated with inflammation, atherosclerosis, immunity and insulin sensitivity. Similarly, adiponectin, an adipocytokine secreted by adipose tissue, has protective roles against the development of insulin resistance, dyslipidaemia and atherosclerosis and exhibits anti-inflammatory properties. The anti-inflammatory activities of adiponectin include inhibition of IL-6 and TNF-induced IL-8 formation, as well as induction of the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Adiponectin levels are also inversely correlated with C-reactive protein (CRP), TNF-alpha and IL-6 levels. Likewise, recent studies have shown a possible correlation between CRP, TNF-alpha and IL-6 and migraine attacks. In addition, insulin sensitivity is impaired in migraine and obesity is a risk factor for the transformation from episodic to chronic migraine. In this review we discuss the basic science of adiponectin and its potential connection to the pathophysiology of migraine. Future research may focus on how adiponectin levels are potentially altered during migraine attacks, and how that information can be potentially translated into migraine therapy.Cephalalgia 06/2007; 27(5):435-46. · 3.43 Impact Factor -
Article: PGE1 inhibits the expression of PAI-1 mRNA induced by TNF-alpha in human mesangial cells.
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ABSTRACT: We examined the effect of PGE1 on the expression of plasminogen activator inhibitor-1 (PAI-1) mRNA induced by tumor necrosis factor-alpha (TNF-alpha) in human mesangial cells, because PAI-1 is one of major factors for the progression of glomerulosclerosis. The expression of PAI-1 mRNA was increased after stimulation with TNF-alpha, and it was diminished by pre-incubation with PGE1. Next, we examined the effect of PGE1 on the phosphorylation of mitogen activated protein kinase (MAPK) family and Akt. TNF-alpha activated the phosphorylation of p44/42 MAPK, p38 MAPK, SAPK/JNK and Akt in mesangial cells. PGE1 inhibited the TNF-alpha induced phosphorylation of SAPK/JNK and Akt, but not p44/42 MAPK and p38 MAPK. The TNF-alpha induced expression of PAI-1 mRNA was not affected by PD98059, an inhibitor of MEK, SB203580, an inhibitor of p38 MAPK, nor LY294002, an inhibitor of PI3 K. However, DMAP, an inhibitor of SAPK/JNK, inhibited the expression of PAI-1 mRNA, suggesting that the TNF-alpha induced expression of PAI-1 mRNA is regulated by the SAPK/JNK dependent pathway in human mesangial cells. By the incubation with H8, an inhibitor of PKA, the inhibitory effect of PGE1 on the expression of PAI-1 mRNA was abolished, suggesting that PGE1 inhibited the PAI-1 mRNA expression via the PKA pathway. Our results suggest that the inhibition of PAI-1 synthesis by PGE1 in human mesangial cells may have therapeutic implications for glomerulosclerosis such as occurs in diabetic nephropathy.Experimental and Clinical Endocrinology & Diabetes 08/2005; 113(7):365-71. · 1.69 Impact Factor
