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Biomedical subjects

Takao Saruta

Publications and source records attributed to Takao Saruta.

At least 19 recordsLinked to original sources
PubMed2006

Impact of angiotensin-converting enzyme inhibition on renal cortical nitrotyrosine content during increased extracellular glucose concentration.

OBJECTIVES: Experiments evaluated the hypothesis that angiotensin-converting enzyme (ACE) inhibition suppresses hyperglycemia-induced nitrotyrosine (NT) production in the renal cortex. DESIGN AND METHODS: Rats were untreated (UNTR, n = 6) or received the ACE inhibitor enalapril (20 mg/kg/day; ENAL, n = 6) for 2 weeks. Renal cortical slices were incubated for 90 min in media containing 5 (normal) or 20 mmol/L (high) glucose. Superoxide anion (O2*-) and nitrate + nitrite (NO(X)) levels were measured in the media. Superoxide dismutase (SOD) activity and NT content were measured in the tissue homogenate. RESULTS: In the UNTR group, high glucose increased O2*- and NO(X) production by the renal cortex (P < 0.05 vs. normal glucose). Likewise, NT content and SOD activity of the renal cortex augmented (P < 0.05 vs. normal glucose). In the ENAL group, O2*- production and NT content were glucose-insensitive, but high glucose exerted an exaggerated impact on NO(X) production and SOD activity (P < 0.01 vs. UNTR in high glucose). CONCLUSION: Accelerated NT content in the renal cortex during high-glucose conditions was prevented by ACE inhibitor treatment. It was suggested that, apart from its anti-hypertensive effect, the mechanism of suppressed NT degradation in the renal cortex by the ACE inhibitor enhances both O2*- degradation per se and antioxidative effects including SOD activation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Dimethylarginine dimethylaminohydrolase 2 increases vascular endothelial growth factor expression through Sp1 transcription factor in endothelial cells.

OBJECTIVE: Dimethylarginie dimethylaminohydrolase (DDAH) is a degrading enzyme for asymmetrical dimethylarginine, an endogenous NO synthase inhibitor. The molecular mechanism for DDAH-induced vascular endothelial growth factor (VEGF) expression was examined. METHODS AND RESULTS: Although the transfection of expression vectors for 2 isoforms of DDAH, DDAH1, or DDAH2 increased DDAH activity in bovine aortic endothelial cells and human umbilical vein endothelial cells, expression and secretion of VEGF were increased only in DDAH2-transfected cells. Knocking down the DDAH2 gene reduced VEGF production, and DDAH2 overexpression enhanced both proliferation and migration of endothelial cells. The VEGF promoter activity was increased by DDAH2 transfection, which was not blocked by an NO synthase (NOS) inhibitor but required the Sp1 sites. DDAH2 overexpression increased nuclear protein levels bound to Sp1 oligonucleotides in endothelial cells. Sp1 small interfering RNA blocked DDAH2-induced upregulation of VEGF. DDAH2 transfection increased nuclear and threonine-phosphorylation levels of Sp1 in a protein kinase A (PKA)-dependent manner. Protein-protein interaction between DDAH2 and PKA was enhanced in DDAH2-transfected cells. CONCLUSIONS: DDAH2 upregulated the expression of VEGF through Sp1-dependent and NO/NOS system-independent promoter activation. DDAH2-increased Sp1 DNA binding activity was PKA dependent. These mechanisms may provide a novel therapeutic strategy for VEGF-related vasculopathies such as atherosclerosis.

Amidohydrolases↗
PubMed2006

Molecular mechanisms and therapeutic strategies of chronic renal injury: role of rho-kinase in the development of renal injury.

Rho/Rho-kinase plays an important role not only in the vasoconstrictor mechanism but also in cellular morphology, motility, adhesion, and proliferation. This pathway also serves to modulate the structure and function of various kidney cells including tubular epithelial cells, mesangial cells, and podocytes. The inhibition of the Rho/Rho-kinase pathway elicits marked increases in renal blood flow in vivo and dilates both afferent and efferent arterioles preconstricted by angiotensin II in vitro. In renal injury, intrarenal angiotensin II is reported to be activated, which subsequently would upregulate the Rho-kinase pathway. A selective Rho-kinase inhibitor, fasudil, has recently been shown to improve renal damage resulting from hypertensive glomerulosclerosis, unilateral ureteral obstruction (for interstitial renal fibrosis) and subtotal nephrectomy. Of interest, fasudil upregulated the expression of p27(kip1), a cyclin-dependent kinase inhibitor, and increased the p27(kip1) immuno-positive cells in both glomeruli and tubulointerstitium with the use of immunohistochemistry. Collectively, the Rho-kinase pathway is involved in the pathogenesis of renal injury. Clinical application of this type of therapy however awaits further investigations.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Effects of the angiotensin receptor blocker candesartan on arterial stiffness and markers of extracellular matrix metabolism in patients with essential hypertension.

Laboratory studies have shown that angiotensin receptor blockers (ARBs) can affect extracellular matrix (ECM) metabolism and thereby have a beneficial effect on vascular remodeling. The aim of this study was to examine the clinical effects of the ARB candesartan cilexetil on serum markers of synthesis and degradation of ECM, as well as their relation to changes in arterial stiffness in hypertensive patients. Twenty-three patients with essential hypertension were recruited for this study. Markers related to ECM synthesis and degradation (procollagen type 1 propeptide [PIP], procollagen type III propeptide [PIIIP], matrix metalloproteinase-3 [MMP-3, stromelysin-1], tissue inhibitor of matrix metalloproteinases [TIMP-1], and hyaluronic acid [HA]) were examined both before and after one year of treatment with candesartan. Pulse-wave velocity [PWV] and ankle-brachial pressure index [ABI] were measured two months (i.e., after achieving blood pressure reduction) and one year after the initiation of therapy. PWV values after one year of treatment with ARB were significantly decreased compared to previous values, whereas ABI values were unchanged. Treatment with ARB was also associated with a significant decrease in serum PIIIP values and an increase in serum stromelysin-1, whereas changes in PIP, TIMP-1, and HA did not achieve statistical significance. A significant relationship was found between the changes in PWV and the changes in stromelysin-1 levels after correction for blood pressure and heart rate (p = 0.02). These results suggest that the treatment for just one year with ARB results in significant changes in markers of ECM metabolism as well as PWV. These effects on ECM metabolism could have a beneficial effect in decreasing vascular pathology in patients with essential hypertension.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

A case report of progressive multifocal leukoencephalopathy in a human T-cell lymphotropic virus type 1-infected hemodialytic patient.

We experienced a case manifesting progressive multifocal leukoencephalopathy (PML) in a hemodialytic patient with hepatitis C virus-induced liver cirrhosis and human T-cell lymphotropic virus type-1 (HTLV-1)-associated uveitis. A 57-year-old male patient had received chronic hemodialysis therapy for 10 years, during which he received multiple blood transfusions and HTLV-1-associated uveitis developed. He complained of visual disturbance and disorientation. Brain CT scan showed diffuse and multifocal low density areas in occipital and temporal lobes, with gray matter relatively spared. MRI imaging showed high intensity lesions in the same areas. Cerebrospinal fluid culture was negative, but using nested PCR, rearranged regulatory region of JC virus DNA was detected. His consciousness level gradually deteriorated and complete paraplegia developed. Seven months after admission, he died of pneumonia. An autopsy confirmed the diagnosis of PML. Notably, mononuclear cell infiltration, gliosis and demyelinating lesions but no nuclear inclusion bodies were observed in the thoracic cord, which suggested HTLV-1-associated myelopathy. Because JC virus is activated under immunocompromised conditions, precipitating factors in this case appear multifactorial; depressed immune system induced by chronic hemodialysis as well as blood-borne hepatitis C virus/HTLV-1 infection might contribute to the activation of dormant JC virus and the development of florid clinical manifestation of PML.

Diffusion Magnetic Resonance Imaging↗
PubMed2006

Combination therapy with aldosterone blockade and renin-angiotensin inhibitors confers organ protection.

There is increasing evidence that aldosterone exerts major adverse cardiovascular effects through classical mineralocorticoid receptors (MR) in nonepithelial tissues such as the brain and heart. This nonepithelial role of aldosterone has been underscored by the recent Randomized Aldactone Evaluation Study (RALES) and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS). These studies also showed that when using MR antagonist as an "organ protecting" drug, further organ protection could be derived by the addition of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 receptor blocker (ARB). The long-term effect of aldosterone was not inhibited in some subjects, so the possibility of organ damage due to so-called "breakthrough" aldosterone cannot be ignored. Nonepithelial MR-mediated effects played a major role in this aldosterone effect. These effects can be inhibited by MR antagonist at a small dose, not lower blood pressure. Therefore, the idea is now to combine a small dose of MR antagonist with an ACE inhibitor or ARB. However, warnings have been given recently due to the emergence of hyperkalemia and other adverse effects associated with inappropriate combination therapy. It is important to note that, if the eligibility criteria of RALES and EPHESUS are fulfilled, the potassium level will rarely become problematic. Therefore, the recent increase in the incidence of adverse effects can be attributed to the incorrect application of combination therapy. Elderly patients or those with dehydration, renal dysfunction, and aggravated heart failure require further close monitoring or termination of spironolactone administration. The combination of an MR antagonist and renin-angiotensin inhibitors should be a useful strategy if subjects are carefully selected, and carefully monitored. Adverse effects will occur only if the usage recommendations based on previous researches are not followed.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Comparison of health costs associated with treatment of hypertension with a calcium channel blocker and angiotensin-converting enzyme inhibitor in the United States and Japan.

Hypertension is prevalent in over 25% of populations in developed countries, and poses an increasing economic burden on health resources. Therefore it is predicted that future medical treatment of hypertension will be increasingly affected by cost considerations. Several classes of antihypertensive drugs are used as first-line agents for the treatment of hypertension, but the economic impact of using these agents in different countries remains to be addressed. In this study, we compared health costs associated with treatment of hypertension using the calcium channel blocker amlodipine and the angiotensin-converting enzyme inhibitor enalapril in the US and Japan. Pharmaceutical costs and hospitalization costs were analyzed from established databases. The data for the prevalence of myocardial infarction and stroke were derived from the Framingham study and the Hisayama study. Analysis of the economic impacts using relative risk differences between the calcium channel blocker and angiotensin-converting enzyme inhibitor together with regional hospitalization costs resulted in an apparent 11.2 billion yen health cost reduction in favor of the calcium channel blocker in the case of Japan, in contrast to an apparent 5.7 billion yen reduction in favor of the angiotensin-converting enzyme inhibitor in the case of the US. The trends in Japan for 2000 and 2004 were similar. These results suggest that there are regional differences in the health costs associated with different classes of hypertensive agents, which could affect national policies on the choice of antihypertensive drugs. It is predicted that future treatment of hypertension will be increasingly tailored to the epidemiologic profiles and medical costs of individual communities.

Amlodipine↗
PubMed2005

Anion-exchange blocker enhances cytoplasmic vacuole formation and cell death in serum-deprived mouse kidney epithelial cells in mice.

An anion exchange blocker, DIDS, exhibits anti-apoptotic activity in response to several apoptotic stimuli, but has an opposite effect when apoptosis is induced by serum deprivation. After adding DIDS, serum-deprived MCT cells exhibited vacuole formation in their cytoplasm and underwent cell death. Caspase activity increased with the addition of DIDS to serum-deprived MCT cells, but Z-Asp-CH2-DCB, a caspase inhibitor, did not inhibit cell death in DIDS-treated, serum-deprived MCT cells. Cathepsin is considered to be important for vacuole formation and cell lysis, and pepstatin A, a cathepsin D inhibitor, partially inhibited vacuole formation in DIDS-treated, serum-deprived MCT cells, although caspase activation was not inhibited. 3-Methyladenin inhibited vacuole formation and cell death in DIDS-treated, serum-deprived MCT cells. These results suggest that DIDS-treated serum-deprived MCT cells undergo autophagy, not apoptosis.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2005

CXCL10 DNA vaccination prevents spontaneous diabetes through enhanced beta cell proliferation in NOD mice.

CXCL10, a chemokine for Th1 cells, is involved in the pathogenesis of various Th1-dominant autoimmune diseases. Type 1 diabetes is considered to be a Th1-dominant autoimmune disease, and a suppressive effect of CXCL10 neutralization on diabetes development has been reported in a cyclophosphamide-induced accelerated diabetes model through induction of beta cell proliferation. However, intervention in a diabetes model might bring about opposite effects, depending on the timing, amount, or method of treatment. In the present study, we examined the effect of CXCL10 neutralization in a "spontaneous diabetes" model of NOD mice, using CXCL10 DNA vaccination (pCAGGS-CXCL10). pCAGGS-CXCL10 treatment in young NOD mice induced the production of anti-CXCL10 Ab in vivo and suppressed the incidence of spontaneous diabetes, although this treatment did not inhibit insulitis or alter the immunological response. pCAGGS-CXCL10 treatment enhanced the proliferation of pancreatic beta cells, resulting in an increase of beta cell mass in this spontaneous diabetes model as well. Therefore, CXCL10 neutralization is suggested to be useful for maintaining beta cell mass at any stage of autoimmune diabetes.

Animals↗
PubMed2005

Significance of serum CXCL10/IP-10 level in type 1 diabetes.

Although we have previously reported an elevated serum level of CXCL10/IP-10 (CXCL10), a Th1 chemokine, in type 1 diabetic patients, little is known about the origin of serum CXCL10 and its significance in type 1 diabetes. Therefore, we examined serum CXCL10 level in NOD mice in association with the expression level of CXCL10 in the pancreas, pancreatic lymph nodes (LN) and spleen. Serum CXCL10 level increased over time towards the onset of diabetes, and was significantly higher in the "diabetic" period (20 and 24 weeks of age and at onset of diabetes) than in the "pre-diabetic" period (4, 8 and 16 weeks of age). Moreover, serum CXCL10 level was associated with CXCL10 and CXCR3 mRNA level in pancreatic LN. Furthermore, it seemed that serum CXCL10 level increased just before (or at) the onset of overt diabetes. These results suggest that serum CXCL10 level may reflect accumulation of Th1 lymphocytes in pancreatic LN, and measurement of serum CXCL10 level may be useful to assess the pathophysiology of the disease course in type 1 diabetes.

Animals↗
PubMed2005

Rho-kinase as a molecular target for insulin resistance and hypertension.

Rho-kinase plays an important role in hypertension and is reported to interfere with insulin signaling through serine phosphorylation of insulin receptor substrate-1 (IRS-1) in cultured vascular smooth muscle cells. We therefore examined the role of Rho-kinase in the development of insulin resistance in Zucker obese rats. In skeletal muscles and aortic tissues of Zucker obese rats, activation of RhoA/Rho-kinase was observed. Long-term Rho-kinase inhibition by 4 wk treatment with fasudil (a Rho-kinase inhibitor) not only reduced blood pressure but corrected glucose and lipid metabolism, with improvement in serine phosphorylation of IRS-1 and insulin signaling in skeletal muscles. Direct visualization of skeletal muscle arterioles with an intravital CCD videomicroscope demonstrated that both acetylcholine- and sodium nitroprusside-induced vasodilations were blunted, which were restored by the fasudil treatment. Furthermore, both fasudil and Y-27632 prevented the serine phosphorylation of IRS-1 induced by insulin and/or tumor necrosis factor-alpha in skeletal muscle cells. Collectively, Rho-kinase is responsible for the impairment of insulin signaling and may constitute a critical mediator linking between metabolic and hemodynamic abnormalities in insulin resistance.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗