Search PubMed⌕ Search

Biomedical subjects

Sadayoshi Ito

Publications and source records attributed to Sadayoshi Ito.

At least 19 recordsLinked to original sources
PubMed2006

Expression of cytochrome P-450 4 enzymes in the kidney and liver: regulation by PPAR and species-difference between rat and human.

Members of the cytochrome P-450 4 (CYP4) family catalyze the omega-hydroxylation of fatty acids, and some of them have the PPAR response element in the promoter area of the genes. The localization of CYP4A and PPAR isoforms and the effect of PPAR agonists on CYP4A protein level and activity were determined in rat kidney and liver. Immunoblot analysis showed that CYP4A was expressed in the liver and proximal tubule, with lower expression in the preglomerular microvessel, glomerulus and thick ascending limb (TAL), but the expression was not detected in the collecting duct. PPARalpha was expressed in the liver, proximal tubule and TAL. PPARgamma was expressed in the collecting duct, with lower expression in the TAL, but no expression in the proximal tubule and liver. The PPARalpha agonist clofibrate induced CYP4A protein levels and activity in the renal cortex and liver. The PPARgamma agonist pioglitazone did not modulate them in these tissues. The localization of CYP4A and CYP4F were further determined in human kidney and liver by immunohistochemical technique. Immunostainings for CYP4A and CYP4F were observed in the hepatocytes of the liver lobule and the proximal tubules, with lower stainings in the TALs and collecting ducts, but no staining in the glomeruli or renal vasculatures. These results indicate that the inducibility of CYP4A by PPAR agonists in the rat tissues correlates with the expression of the respective PPAR isoforms, and that the localization of CYP4 in the kidney has a species-difference between rat and human.

Animals↗
PubMed2006

Angiotensin II type 1 receptor blockers reduce urinary oxidative stress markers in hypertensive diabetic nephropathy.

We tested the hypothesis that blockade of angiotensin II type 1 receptors reduces oxidative stress markers in parallel with urinary albumin and type IV collagen excretions. Sixty-six diabetic patients with nephropathy were randomly assigned to either the angiotensin II receptor blocker (ARB; n=33) or trichlormethiazide (n=33) group. The majority of patients had been treated with angiotensin-converting enzyme inhibitors or calcium channel blockers for > or =1 year before the present study. Reduction of blood pressure was not different between the 2 groups, and HbA1c levels did not change over the study period (8 weeks). Treatment with ARB (candesartan 8 mg/day, n=11 or valsartan 80 mg/day, n=22) for 8 weeks reduced the levels of plasma monocyte chemoattractant protein 1, interleukin 6, urinary 8-epi-prostaglandin F2alpha, 8-hydroxydeoxyguanosine, albumin, and type IV collagen, whereas the levels of these markers were not altered with trichlormethiazide (2 mg/day). Significant correlation was observed between the reduction of the urinary 8-epi- prostaglandin F2alpha and 8-hydroxydeoxyguanosine and those of the urinary albumin and type IV collagen. Subjects with large oxidative stress had large reduction rates because of ARB administration and showed large urinary albumin suppression. These results suggest that ARBs reduce oxidative stress and inflammation in diabetic patients independent of their effects on blood pressure. In addition, increases in oxidative stress caused by angiotensin II may play an important role in the progression of diabetic nephropathy. Our results may help to explain the clinical observation that ARB reduces urinary albumin excretion very efficiently in some patients but not in others.

Adult↗
PubMed2006

Molecular mechanisms and therapeutic strategies of chronic renal injury: physiological role of angiotensin II-induced oxidative stress in renal medulla.

Renal medullary circulation has now been found to play a fundamental role in regulating long-term blood pressure control and fluid balance. Elevation of superoxide or reduction of nitric oxide (NO) in renal medulla decreases medullary blood flow and Na excretion, resulting in sustained hypertension. Angiotensin II (Ang II)-induced interaction of superoxide and NO was determined in thin tissue strips isolated from the renal outer medullary region of Sprague-Dawley rats using fluorescent microscopy techniques. Ang II can induce diffusion of NO, but not superoxide, from the medullary thick ascending limb (mTAL) to the surrounded vasa recta. However, when NO is reduced by the NO scavenger carboxy-PTIO, Ang II can induce superoxide diffusion from mTAL to vasa recta pericytes. Therefore, the physiological action of oxidative stress in renal medullary region is demonstrated as balance of superoxide and NO diffusion ("tubulo-vascular cross-talk"). These results explain how chronically hypoxic medulla can maintain blood flow. In other studies using chronically instrumented rats, we found that nearly 70% of Ang II-induced medullary renal injury was dependent on pressure determined by servo-control of renal perfusion pressure, whereas 30% of the injury was non-hemodynamic. We conclude that oxidative stress within the renal medulla can induce hypertension and also make the kidney functionally more vulnerable to the effects of Ang II.

Angiotensin II↗
PubMed2006

Preventing microalbuminuria in patients with diabetes: rationale and design of the Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study.

Diabetic nephropathy has developed into a worldwide epidemic and is responsible for the majority of end-stage renal disease in most countries. Antihypertensive treatment slows the progression of the disease. In addition, blockade of the renin-angiotensin system reduces the degree of albuminuria and angiotensin II receptor blockers (ARBs) have been shown to delay the progression from microalbuminuria to overt proteinuria in patients with diabetes. However, few studies have examined whether the initial stage of diabetic nephropathy (i.e. the development of microalbuminuria) in patients with type 2 diabetes can be slowed or prevented by ARB treatment. The Randomised Olmesartan And Diabetes MicroAlbuminuria Prevention (ROADMAP) study is a placebo-controlled, multicentre, double-blind, parallel group study investigating the effect of the ARB, olmesartan medoxomil, on the incidence of microalbuminuria. A total of 4400 type 2 diabetes patients with normoalbuminuria will be randomized to treatment with 40 mg of olmesartan medoxomil once daily or placebo. Goal blood pressure will be 130/80 mmHg. The primary endpoint of the study is the occurrence of microalbuminuria. In ROADMAP, we will also assess as secondary endpoints the effects of olmesartan on fatal and non-fatal cardiovascular events in patients with diabetes. In addition, within subgroups of the ROADMAP patients, the effects of olmesartan on retinopathy and other microvascular circulations will be analysed. The study is expected to last a median of 5 years. The ROADMAP study will answer the question whether an ARB can prevent or delay the onset of microalbuminuria and whether this translates into protection against cardiovascular events and renal disease.

Adolescent↗
PubMed2005

Methylmercury inhibits type II 5'-deiodinase activity in NB41A3 neuroblastoma cells.

Methylmercury (MeHg) is a well-known neurotoxicant and prenatal exposure to MeHg results in severe brain damage. Since MeHg has a high affinity for thiol groups, we sought to determine whether MeHg inhibited type II iodothyronine deiodinase (D2) activity, by which prohormone thyroxine (T4) is converted to active thyroid hormone, 3,5,3'-triiodothyronine (T3) in the brain, using NB41A3 mouse neuroblastoma cells. In MeHg-treated cells, D2 activity was inhibited in a dose- and time-dependent manner; relatively low concentrations of MeHg (30 nM) inhibited D2. Kinetic analysis using a double reciplocal plot of D2 activity revealed competitive inhibition by MeHg. DTT protected D2 from MeHg when cells were incubated with both MeHg and DTT or when MeHg was added to the assay buffer containing DTT and cell sonicates from untreated cells. Removal of MeHg from culture medium did not recover D2 activity. These results demonstrate that MeHg inhibited D2 activity in NB41A3 cells and the selenocysteine in the catalytic subunit of D2 may be involved in the inhibitory action of MeHg. Further our results suggest that T3 deficiency due to D2 inhibition in the brain may be involved in the neurotoxicity of MeHg.

Animals↗
PubMed2005

Characterization of the organic cation transporter SLC22A16: a doxorubicin importer.

Specific efflux transporters, such as P-glycoprotein, have been shown to confer drug resistance by decreasing the intracellular accumulation of anticancer drugs. Understanding influx transporters, as well as efflux transporters, is essential to overcome this resistance. We report the expression profile and pharmacological characterization of an organic cation transporter, SLC22A16. The results of our experiments indicate that SLC22A16 is a mediator of doxorubicin uptake in cancer cells. Quantitative real-time RT-PCR analyses show that SLC22A16 is expressed in primary samples taken from patients with acute leukemia. Xenopus oocytes injected with SLC22A16 cRNA import doxorubicin, a widely used anticancer drug for hematological malignancies, in a saturable and dose-dependent manner. The apparent Km value for doxorubicin import was 5.2+/-0.4 microM. In cytotoxic assays, stable transfectants of leukemic Jurkat cells overexpressing SLC22A16 cells became significantly more sensitive to doxorubicin (2 microM) treatment. Characterization of SLC22A16 will help in designing novel therapies targeting hematological malignancies.

Antibiotics, Antineoplastic↗
PubMed2005

Upregulation of nitric oxide production in vascular endothelial cells by all-trans retinoic acid through the phosphoinositide 3-kinase/Akt pathway.

BACKGROUND: A natural retinoid all-trans retinoic acid (ATRA) contains various beneficial effects on vasculature, including suppression of neointima formation after balloon injury. However, little is known about the effects of ATRA on vascular endothelial function. We therefore studied its role in nitric oxide (NO) production of vascular endothelial cells (ECs). METHODS AND RESULTS: Human dermal microvascular ECs, human umbilical vein ECs, and SV40-transformed rat lung vascular ECs were incubated with or without ATRA (1 micromol/L) for 48 hours. Their NO production was determined with the use of a fluorescent NO indicator, diaminofluorescein-2 diacetate. ATRA significantly increased their basal as well as acetylcholine-induced NO production. Treatment with Nomega-nitro-L-arginine methyl ester or carboxy-PTIO suppressed their fluorescence. Increase of NO production was also observed by incubation with retinoic acid receptor (RAR) agonist Am580. ATRA-induced NO increase was abolished by coincubation with RAR antagonist LE540. Moreover, the NO increase was completely inhibited by the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin and LY294002. ATRA as well as Am580 enhanced endothelial NO synthase (eNOS) phosphorylation at Ser-1177 as well as Akt phosphorylation at Ser-473 without changing their protein expression. Overexpression of dominant-negative Akt inhibited the eNOS phosphorylation. Moreover, ATRA increased PI3K activity as well as PI3K catalytic subunit p110beta protein expression, which was completely inhibited by LE540 treatment. Real-time polymerase chain reaction analyses demonstrated that ATRA increased PI3K catalytic subunit p110beta mRNA expression without affecting its stability. Finally, ATRA-induced NO increase was observed in COS-1 cells transfected with wild-type eNOS and RARalpha, but not with mutated eNOS whose Ser-1177 was substituted. CONCLUSIONS: ATRA increases NO production by eNOS phosphorylation through RAR-mediated PI3K/Akt pathway activation in vascular ECs and possibly plays beneficial roles in vascular endothelium. Retinoids may therefore be candidates as novel therapeutic agents against vascular disorders with endothelial damage.

Cells, Cultured↗
PubMed2005

PDZ-binding and di-hydrophobic motifs regulate distribution of Kir4.1 channels in renal cells.

It was shown previously that the carboxyl-terminal cytoplasmic portion of Kir4.1 determines the localization of basolateral K+ channel in renal distal tubules, which is composed from the assembly of Kir4.1 and Kir5.1. For clarifying the signals for this localization, specific sequence motifs of Kir4.1 were sought. In HEK293T cells, where Kir4.1 showed linear expression on the cell surface, disruption of the carboxyl-terminal PDZ-binding motif induced mostly clustered distribution but did not reduce whole-cell channel activity. Point mutation analysis revealed that serine377 in this motif was responsible for the surface vicinity expression. Disruption of the di-hydrophobic array of valine333/valine334 induced diffuse cytoplasmic distribution and diminished channel activity. Both valine333 and valine334 contributed to this effect. In contrast to the di-hydrophobic motifs of other membrane proteins that facilitate the sorting, valine333/valine334 supported the cell-surface retention. Because both the PDZ-binding and di-hydrophobic motifs participated in the basolateral expression of both Kir4.1 homomer and Kir5.1/Kir4.1 heteromer in MDCK cells, they are thought to be responsible for the localization of basolateral K+ channel in renal distal tubules.

Amino Acid Motifs↗
PubMed2005

Cytochrome P-450-dependent metabolism of arachidonic acid in the kidney of rats with diabetes insipidus.

This study compared the renal metabolism of arachidonic acid in Brattleboro (BB) (vasopressin deficient) and Long-Evans (LE) control rats and the effects of a cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) on renal function in these animals. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) by renal cortical and outer medullary microsomes was significantly greater in BB than in LE rats (155 +/- 16 vs. 92 +/- 13 and 59 +/- 7 vs. 33 +/- 3 pmol.min(-1).mg protein(-1)). Renal cortical epoxygenase activity was not different in these strains. The expression of CYP4A proteins was 58 and 78% higher in the renal cortex and outer medulla of BB than in LE rats. Chronic treatment of BB rats with a vasopressin type 2 receptor agonist for 1 wk normalized the renal production of 20-HETE. Chronic blockade of the formation of 20-HETE and EETs with ABT had little effect on renal function in LE rats. However, urine flow increased by 54% and urine osmolarity decreased by 33% in BB rats treated with ABT. Plasma levels of oxytocin fell significantly from 7.2 +/- 1.3 to 3.9 +/- 1.0 pg/ml. The effects of ABT in BB rats were attenuated by chronic infusion of oxytocin (0.7 ng.min(-1).100 g(-1)) to maintain fixed high plasma levels of this hormone. These results indicate that the expression of CYP4A protein and the renal formation of 20-HETE are elevated in the kidney of BB rats due to a lack of vasopressin and that chronic blockade of the formation of 20-HETE and EETs with ABT promotes water excretion in vasopressin-deficient BB rats by reducing the circulating levels of oxytocin, which is a weak vasopressin agonist.

8,11,14-Eicosatrienoic Acid↗
PubMed2005

[Hypertension].

Explore the source record for details and available documents.

Humans↗
PubMed2005

Steroid resistance in prolonged type I membranoproliferative glomerulonephritis and accelerated disease remission after steroid withdrawal.

Two cases of severe proteinuria and hypocomplementemia were referred to our out patient clinic for continuous follow-up. Initial onset of clinical symptoms was at the age of 15 years in both cases. They had already been diagnosed as type I membranoproliferative glomerulonephritis (type I MPGN) by renal biopsy when oral prednisolone administration had been initiated. Several courses of steroid pulse therapy were performed for the flares of the disease, resulting in only temporary amelioration of renal symptoms. Percutaneous renal biopsy was performed during admission on both cases, showing severe glomerular and tubulointerstitial damages, in addition to typical type I MPGN findings such as mesangial cells and matrix interposition and subendothelial deposits. Because the continuous administration of steroid for more than 10 years did not ameliorate the clinical symptoms, steroid was markedly reduced or stopped in these cases. Such withdrawal from steroid therapy accelerated the amelioration of renal symptoms, including decrease in proteinuria, elevation of plasma protein and complement levels, and disappearance of generalized edema. The clinical courses of these cases indicate clinical choice of withdrawal from steroid therapy as one of the treatments in prolonged type I MPGN, which presents in childhood and shows steroid resistance.

Adolescent↗
PubMed2005

Cutting balloon angioplasty of resistant renal artery stenosis caused by fibromuscular dysplasia.

Balloon angioplasty is an established intervention to treat renovascular hypertension. Conventional balloon angioplasty is usually effective in cases of renovascular hypertension caused by fibromuscular dysplasia. In the present report, we describe two cases of renovascular hypertension caused by fibromuscular dysplasia in which stenotic lesions were resistant to conventional balloon angioplasty but were successfully managed by a cutting balloon. After cutting balloon angioplasty, systemic blood pressure was normalized in both patients, without the use of antihypertensive agents. Angioplasty by using a cutting balloon is a new therapeutic choice against renal artery stenosis that is resistant to dilation by a conventional balloon.

Adolescent↗
PubMed2005

Plasma renin activity revealed renal artery stenosis concealed by aneurysms.

We describe a case of renovascular hypertension with renal artery stenosis concealed by aneurysms. Arteriography demonstrated no apparent renal artery stenosis, but did reveal aneurysms on the left renal artery. Captopril-loaded renoscintigraphy could not detect disturbed renal perfusion. High basal and exaggerated plasma renin activity after captopril administration were the only clues indicating renovascular hypertension. A reduction of the systemic blood pressure and normalized plasma renin activity after resection of the aneurysms confirmed preoperative renovascular hypertension. Fibromuscular dysplasia was an underlying cause of the arterial deformity. In cases of hypertension accompanied by renal artery aneurysms, the captopril-challenge test can be a useful tool to detect renal artery stenosis concealed by the aneurysms.

Adult↗