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Hirokazu Okada

Publications and source records attributed to Hirokazu Okada.

At least 19 recordsLinked to original sources
PubMed2006

Impact of selectin gene polymorphisms on rapid progression to end-stage renal disease in patients with IgA nephropathy.

OBJECTIVE: It is evident that leukocyte infiltration plays an important role in the pathogenesis of IgA nephropathy (IgAN). Selectin is one of the key adhesion molecules involved in leukocyte infiltration. Recent studies demonstrated a significant association between the selectin gene polymorphisms and susceptibility to IgAN. However, the impact of selectin gene polymorphisms on the progression to end-stage renal disease (ESRD) has not been studied. PATIENTS AND METHODS: To evaluate the influence of the selectin gene polymorphisms on the progression of IgAN, we designed specific primers for PCR genotyping and analyzed the association of selectin gene polymorphisms with the declining rate in renal function to its ESRD. RESULTS: A total of 61 hemodialysis patients were enrolled in the study. The mean age at renal biopsy was 33.0+/-13.3 years old, and the mean age at the start of hemodialysis was 41.2+/-13.8 years old. The mean interval between the time points of renal biopsy and the start of hemodialysis was 8.2+/-6.5 years (ranging from 0 to 33 years). The interval was significantly longer in IgAN patients with a homoallele of C in C1402T, C1402/C1402, of the E-selectin gene, or a homoallele of C in C712T, C712/C712, of the L-selectin gene compared to others. The haplotype, which is a combination of C1402/C1402 and C712/C712, is able to distinguish the group that is at least a better prognosis than the severest prognostic one. CONCLUSION: This study provides a possible association between the selectin gene polymorphisms and the rapid progression to ESRD in IgAN patients.

Adult↗
PubMed2006

Dexamethasone induces connective tissue growth factor expression in renal tubular epithelial cells in a mouse strain-specific manner.

Connective tissue growth factor (CTGF), a downstream mediator of transforming growth factor-beta1, mediates mesangial cell/fibroblast proliferation and extracellular matrix production by renal cells. Here, we show that renal tubular epithelial cells from patients with minimal change nephritic syndrome produced CTGF after glucocorticoid treatment. In addition, the glucocorticoid dexamethasone (DEX) increased CTGF mRNA levels in the kidneys of C57B6 but not SJL mice and produced intermediate CTGF mRNA levels in the kidneys of F1 (C57B6 x SJL) mice, midway between the levels found for parental strains. DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA. Transient transfection experiments using luciferase reporter constructs bearing CTGF promoter fragments revealed that the -897- to -628-bp fragment contained DEX-responsive positive regulatory elements, which were active in mProx24 but not MCT cells. Long-term DEX treatment resulted in fibronectin deposition in the kidneys of C57B6 but not SJL mice, and this effect was inhibited by co-administration of CTGF anti-sense oligodeoxynucleotides. Thus, glucocorticoid-induced renal fibrogenesis seems to be influenced by genetic background, with the critical DEX-responsive elements in the -897- to -628-bp region of the CTGF promoter.

Adolescent↗
PubMed2006

A possible anti-inflammatory role of angiotensin II type 2 receptor in immune-mediated glomerulonephritis during type 1 receptor blockade.

We previously reported that angiotensin II type 1 receptor (AT1R) blockade attenuates renal inflammation/fibrogenesis in immune-mediated glomerulonephritis via angiotensin II type 2 receptor (AT2R). In the present study, further in vivo experiments revealed that AT2R was expressed in tubular epithelial cells of nephritic kidneys in mice, and feedback activation of the renin-angiotensin system during AT1R blockade significantly reduced p-ERK, but not intranuclear nuclear factor-kappaB, levels via AT2R. This led to reduction in mRNA levels of the proinflammatory mediator monocyte chemoattractant protein-1 and overall interstitial inflammation and subsequent fibrogenesis. Specific blockade of ERK expression in tubular epithelium by anti-sense oligodeoxynucleotides also attenuated interstitial inflammation, mimicking the anti-inflammatory action of AT2R in nephritic kidneys. Alternatively, we succeeded in confirming such an AT(2)R function by demonstrating that AT1R blockade did not confer renoprotection in nephritic, AT2R gene-deficient mice. Additional in vitro experiments revealed that AT2R activation did not affect nuclear factor-kappaB activation by tumor necrosis factor-alpha in cultured tubular epithelial cells, although it inhibited ERK phosphorylation, which reduced monocyte chemoattractant protein-1 mRNA levels. These results suggest that feedback activation of AT2Rs in tubular epithelium of nephritic kidneys plays an important role in attenuating interstitial inflammation.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2006

Efficacy and safety of meropenem plus tobramycin followed by meropenem plus vancomycin for treating peritonitis in patients on continuous ambulatory peritoneal dialysis.

Peritonitis is a serious complication in patients on peritoneal dialysis. We examined the efficacy of MTV therapy [first 7 days: meropenem 0.5 g intravenously (IV) twice daily, plus tobramycin 15 mg intraperitoneally (IP) in every dialysis bag; next 7 days: meropenem 0.5 g IV twice daily, plus vancomycin 8 mg/kg IP in every bag after a 1-g loading dose] on peritonitis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD), comparing it with the treatment previously recommended by the International Society for Peritoneal Dialysis (combination of first-generation cephalosporins and aminoglycosides). We treated 36 CAPD peritonitis episodes with MTV therapy. Outcome measures were primary response rate at day 14 and relapse rate within 28 days after the start of antibiotic therapy. The primary response rate was 34/36 (94.4%). No patients treated with MTV therapy required catheter removal. We observed no serious side effects in these patients. We conclude that MTV therapy may be an even better choice of treatment for peritonitis in patients on CAPD than was the previous empirical treatment (combination of first-generation cephalosporin and aminoglycosides).

Anti-Bacterial Agents↗
PubMed2006

Long-term follow-up of patients treated with a combination of continuous ambulatory peritoneal dialysis and hemodialysis.

Continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) both have advantages in the treatment of patients with renal failure. In CAPD, solute removal is sometimes insufficient in patients who have a relatively large muscle mass that produces high levels of creatinine. To compensate for this deficiency, frequent exchanges and large dialysate volumes are required. We previously reported that once-weekly HD helps CAPD patients who experience insufficient solute removal. In the present study, we followed, for more than 3 years, 9 CAPD patients who underwent additional weekly HD. Add-on HD therapy significantly increased the subjects' weekly peritoneal creatinine clearance to 45 +/- 3 L (mean +/- standard deviation); these values rose to more than 60 L over the course of the study. Our findings suggest that the combined use of CAPD and HD improves solute clearance in CAPD patients who are insufficiently dialyzed.

Creatinine↗
PubMed2006

Continuous ambulatory peritoneal dialysis is effective for patients with severe congestive heart failure.

Although the use of continuous ambulatory peritoneal dialysis (CAPD) to treat refractory heart failure is not new, in combination with current medical treatment it improves patients'symptoms as well as their cardiac function. We started 16 patients (13 men with a mean age of 66.3 +/- 2.8 years, and 3 women with a mean age of 72 +/- 4.2 years) on CAPD. All patients were symptomatic with congestive heart failure. Mean left ventricular ejection fraction (LVEF) before the start of CAPD was 31% +/- 3%. Introduction to CAPD was associated with a significant improvement in LVEF (to 44% +/- 6%, p < 0.05) and in blood pressure control at 1 year. Also at 1 year, 87% of patients were classified as New York Heart Association grade I or II (maximum possible grade is grade III). These results suggest that CAPD is a treatment of choice for patients suffering from a combination of congestive heart failure and chronic renal insufficiency.

Aged↗
PubMed2006

Risk factors for vascular complications in patients on peritoneal dialysis.

The major cause of death in patients on peritoneal dialysis (PD) is vascular complications, including congestive heart failure, cerebrovascular disease, and myocardial infarction. To clarify the risk factors for vascular complications in patients on PD, we investigated the clinical course of PD in patients with and without cardiovascular and cerebrovascular complications. From among 327 end-stage renal disease (ESRD) patients initiated onto PD from April 1995 to March 2005 in the Kidney and Dialysis Center, Saitama Medical School, 8 developed de novo cardiovascular and cerebrovascular complications (CVD group--mean age: 58.3 +/- 4.9 years; 5 men, 3 women). We compared data pertaining to body weight, blood pressure, blood chemistry, and cardiothoracic ratio (CTR) between the CVD group and an age- and sex-matched control group (n = 8; mean age: 57.5 +/- 4.0 years). At baseline, we observed no significant differences of body weight, blood pressure, CTR, hemoglobin, total cholesterol, triglycerides, HbA1c, or serum albumin between the CVD group and the control group. In the CVD group, 1 month before the onset of CVD, serum albumin was significantly lower than in the control group (2.9 +/- 0.2 g/dL vs. 3.8 +/- 0.1 g/dL, p = 0.0029). Body weight in the CVD group was significantly lower than in the control group (56.8 +/- 2.8 kg vs. 63.0 +/- 2.9 kg, p = 0.0086). No significant differences were observed in blood pressure, CTR, hemoglobin, total cholesterol, triglycerides, or HbA1c between the groups. A decrease in serum albumin after commencement of dialysis is an important risk factor for, and a strong predictor of vascular complications in patients on PD. To help prevent vascular complications, it is important to monitor and manage serum albumin in patients on PD.

Blood Chemical Analysis↗
PubMed2005

Exogenous 5'-nucleotidase improves glomerular autoregulation in Thy-1 nephritic rats.

Experiments were performed to characterize renal hemodynamics in Thy-1 nephritic rats. A monoclonal antibody against Thy-1 was intravenously injected to induce mesangiolysis in rats, and 2 days later renal hemodynamic responses to variations in blood pressure were determined. In the first series of experiments, autoregulation of renal plasma flow (RPF) or glomerular filtration rate (GFR) was impaired in nephritic rats. In response to a reduction in blood pressure (98 +/- 2 to 80 +/- 1 mmHg), both RPF (4.17 +/- 0.63 to 3.20 +/- 0.45 ml x min(-1) x g kidney wt(-1), P < 0.05, n = 6) and GFR (0.88 +/- 0.05 to 0.75 +/- 0.06 ml x min(-1).g kidney wt(-1), P < 0.05) were decreased in nephritic rats. Intravenous administration of furosemide and 30% albumin, both of which inhibit tubuloglomerular feedback, diminished renal autoregulation in control but not nephritic rats. In the second studies, the infusion of 5'-nucleotidase, an enzyme expressed on mesangial cells, into a renal artery ameliorated the magnitude of autoregulatory decrements in GFR in nephritic rats (-16 +/- 5 to -6 +/- 2%, P < 0.05, n = 6), but this enzyme failed to alter renal autoregulation in control rats. In the third studies, the effects of indomethacin were examined in nephritic rats. Inhibition of prostaglandin synthesis reduced RPF (4.07 +/- 0.30 to 1.54 +/- 0.22 ml x min(-1) x g kidney wt(-1), P < 0.05, n = 5) and GFR (1.03 +/- 0.18 to 0.69 +/- 0.13 ml x min(-1) x g kidney wt(-1), P < 0.05) in nephritic rats. However, cyclooxygenase inhibition failed to restore renal autoregulation in nephritic rats. Our results indicate that renal autoregulation is impaired in Thy-1 nephritis. Furthermore, the present data provide evidence that prostanoids contribute to maintain renal circulation in nephritic rats. Finally, our findings suggest that mesangial cells and/or 5'-nucleotidase plays an important role in mediating renal autoregulation.

5'-Nucleotidase↗
PubMed2005

Model-guided microarray implicates the retromer complex in Alzheimer's disease.

Although, in principle, gene expression profiling is well suited to isolate pathogenic molecules associated with Alzheimer's disease (AD), techniques such as microarray present unique analytic challenges when applied to disorders of the brain. Here, we addressed these challenges by first constructing a spatiotemporal model, predicting a priori how a molecule underlying AD should behave anatomically and over time. Then, guided by the model, we generated gene expression profiles of the entorhinal cortex and the dentate gyrus, harvested from the brains of AD cases and controls covering a broad age span. Among many expression differences, the retromer trafficking molecule VPS35 best conformed to the spatiotemporal model of AD. Western blotting confirmed the abnormality, establishing that VPS35 levels are reduced in brain regions selectively vulnerable to AD. VPS35 is the core molecule of the retromer trafficking complex and further analysis revealed that VPS26, another member of the complex, is also downregulated in AD. Cell culture studies, using small interfering RNAs or expression vectors, showed that VPS35 regulates Abeta peptide levels, establishing the relevance of the retromer complex to AD. Reviewing our findings in the context of recent studies suggests how downregulation of the retromer complex in AD can regulate local levels of Abeta peptide.

Adult↗
PubMed2005

Connective tissue growth factor mediates the profibrotic effects of transforming growth factor-beta produced by tubular epithelial cells in response to high glucose.

BACKGROUND: It was reported that connective tissue growth factor (CTGF) was expressed in the tubular epithelial cells of the diabetic kidney. CTGF has, among other factors, been implicated in mediating the downstream, profibrotic effects of transforming growth factor-beta (TGF-beta), though is precise role in interstitial fibrogenesis in the diabetic kidney has not yet been clarified. METHODS: We employed a coculture system involving cultured murine proximal tubular epithelial cells (mProx24) and renal fibroblasts (TFB), as a model of the subepithelial mesenchyme in the kidney in order to examine the profibrotic effects of CTGF derived from mProx24 cells in response to high glucose (30 mM). RESULTS: We showed that glucose stimulated CTGF expression in cultured mProx24 in both a dose- and a time-dependent manner, and that this effect was mediated by increased levels of TGF-beta. We also found that high glucose significantly stimulated TFB cells to produce profibrotic molecules, such as type I collagen, the EIIIA isoform of fibronectin, and plasminogen activator inhibitor-1. The induction of these molecules was both direct and indirect, the latter induction being mediated by mProx24 cell-derived CTGF, which, in turn, was induced by TGF-beta that was produced by the mProx24 cells. CONCLUSIONS: CTGF plays an important role in mediating renal interstitial fibrogenesis in response to high glucose and, as such, is a reasonable target for anti-fibrotic therapy.

Animals↗
PubMed2005

Cellular and molecular pathways that lead to progression and regression of renal fibrogenesis.

Renal fibrosis is a common consequence and often a central feature of all the progressive renal diseases that lead to end-stage renal failure. In comparison to wound healing, during kidney fibrosis the length of the post-inflammatory phase often exceeds and continues unchecked resulting in scar formation. Infiltrating immune cells and a heterogeneous colony of interstitial cells derived from a variety of cellular origins such as resident mesenchymal cells, tubular epithelial cells, circulating fibrocytes, and bone marrow derived stem cells, communicate with each other and with inflamed and surviving parenchymal cells via a network of cytokines and adhesion molecules to populate the renal tubulointerstitial space during early fibrogenesis. Such fibroblasts subsequently secrete abundant extracellular matrix to achieve architectural remodeling in parallel with functional deterioration. Renal fibrosis is a dominant determinant of the clinical outcome of patients and yet for the most part, current therapies are ineffective or only marginally effective. This review highlights recent advances in our understanding of the cellular and molecular events leading to the progression of renal fibrosis.

Animals↗
PubMed2005

[Coronary artery bypass grafting in patients undergoing chronic hemodialysis: importance of wound healing and hypoproteinemia].

OBJECTIVES: Outcome of coronary artery bypass grafting (CABG) in patients undergoing chronic hemodialysis was studied. METHODS: Between January 1996 and August 2004, 49 consecutive hemodialysis patients [38 males and 11 females, mean age 60.0 years (range 47-74 years)] underwent CABG using cardiopulmonary bypass. Duration of hemodialysis was 5.2 years (range 1 month-21 years), and 32 patients were diabetics. Surgery was conducted on the emergency/urgency basis in 12 patients, and intraaortic balloon pumping was placed in 7. Left ventricular ejection fraction was 57.7 +/- 16.3% (range 27-84%). Nine patients underwent concomitant valve surgery. CABG was performed under hypothermic cardiopulmonary bypass and ventricular fibrillation except in one patient, and intraoperative hemodialysis was also performed. Continuous hemodiafiltration was used in the early period after surgery. RESULTS: Number of bypass grafts was 3.0 +/- 1.0 (range 1-6), and the unilateral internal thoracic artery was used in 29 patients. Operation time, cardiopulmonary bypass time, and aorta clamp time were 313 +/- 87, 145 +/- 63, and 49 +/- 43 min, respectively. Diffuse pericardial adhesion was present in five patients. Severely atheromatous ascending aorta precluded manipulation in seven patients. Although the 30-day mortality was 2.0% (one case), all in-hospital mortality over 9 months was 14.3% (seven cases). The morbid events were mediastinitis in seven cases, reexploration for hemorrhage in seven, pneumonia in two, abdominal complication in three, and stroke in one. Delayed onset mediastinitis was common. Risk factors for death were mediastinitis and serum albumin levels < 3.5 g/dl (both p < 0.05), both of which were wound healing-related factors. CONCLUSIONS: CABG in hemodialysis patients carries a high risk. Patients with hypoalbuminemia appear to require special consideration.

Aged↗
PubMed2004

Connective tissue growth factor expressed in tubular epithelium plays a pivotal role in renal fibrogenesis.

Connective tissue growth factor (CTGF) is one of the candidate factors that are thought to mediate the downstream profibrotic action of TGF-beta. However, its precise role in renal interstitial fibrogenesis has not yet been clarified. It was demonstrated previously that CTGF was expressed in tubular epithelial cells that had been engulfed by interstitial fibrosis in the remnant kidney of the subtotal nephrectomy (SNx) model. In the present study, co-cultures of tubular epithelial cells (mProx24) and tubulointerstitial fibroblasts (TFB) that mimic the subepithelial mesenchyme in the kidney were used to study the profibrotic effects of TGF-beta1-induced CTGF. In these co-cultures, TGF-beta1 treatment resulted in significantly increased mRNA levels of type I collagen and fibronectin in the TFB. These effects were both direct and indirect, with the latter being mediated by CTGF derived from the co-cultured mProx24. Then TGF-beta1 transgenic mice were subtotally nephrectomized and treated with CTGF antisense oligodeoxynucleotide, and their kidneys were analyzed for fibrosis. Intravenous administration of CTGF antisense oligodeoxynucleotide significantly blocked CTGF expression in the proximal tubular epithelial cells in the remnant kidney of these animals despite the sustained level of TGF-beta1 mRNA. This reduction in CTGF mRNA level paralleled a reduction in mRNA levels of matrix molecules as well as proteinase inhibitors plasminogen activator inhibitor-1 and tissue inhibitor of metalloproteinase-1, suppressing renal interstitial fibrogenesis. In conclusion, tubular CTGF acts as a downstream mediator of the profibrotic effects of TGF-beta1 in the remnant kidney, which is a promising target for antifibrotic drugs designed to treat TGF-beta1-dependent interstitial fibrosis.

Animals↗
PubMed2004

Angiotensin II type 1 and type 2 receptors reciprocally modulate pro-inflammatory/ pro-fibrotic reactions in activated splenic lymphocytes.

Angiotensin II (Ang II) type 1 receptor (AT1R) has been confirmed to confer renoprotection in the progressive, immune-mediated nephritis in animal models as well as in humans. However, the relative contributions of direct AT1R blockade, indirect counteractivation of Ang II type 2 receptor (AT2R), or both, to renoprotection through AT1R antagonism remains to be clarified. Immunohistochemical studies in the nephritic kidney revealed that tubular epithelial cells and infiltrating immune cells were positive for AT1R and AT2R. In the present study, we investigated the action of Ang II on both receptors on immune cells. A subpopulation of lipopolysaccharide-activated splenic lymphocytes (mixed lymphocyte populations) was positive for AT1R and AT2R. Ang II alone could not induce gene expression of a pro-inflammatory chemokine JE or a pro-fibrotic cytokine transforming growth factor-beta1 in those cells. However, Ang II could significantly suppress the expression of both genes in those cells under AT1R blockade, and this action was mediated through AT2R. Conversely, the pro-inflammatory/pro-fibrotic gene expression could be enhanced by AT2R blockade, and this was mediated through AT1R. AT1R and AT2R expressed in activated immune cells can modulate pro-inflammatory and pro-fibrotic reactions reciprocally. In advanced immune-mediated nephritic kidneys, AT1R antagonism likely confers renoprotection via activation of AT2R.

Animals↗
PubMed2004

Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immune-mediated nephritic kidney through counter-activation of angiotensin II type 2 receptor.

The relative roles of angiotensin II (Ang II) type 1 receptor (AT(1)R) and Ang II type 2 receptor (AT(2)R) in immune-mediated nephritis are unknown, and the effect of the blockade of AT(1)R and its indirect counter-activation of AT(2)R relative to the anti-fibrotic action in this disease is unclear. To address this question, we studied the role of AT(1)R and AT(2)R in anti-glomerular basement membrane nephritis in SJL mice. Groups of mice were treated with either an AT(1)R antagonist (CGP-48933; CGP group), an AT(2)R antagonist (PD-123319; PD group), both (CGP/PD group), or a vehicle (PCt group) from Day 29 to 56. At Day 56 post-treatment, fibrosis-related parameters such as interstitial matrix deposition, and the expression of genes of TGF-beta1, plasminogen activator inhibitor-1, and type I collagen were significantly reduced in the kidney in the CGP group. There were no significant effects on these parameters in the PD group. However, this anti-fibrotic action by CGP-48933 was totally abolished by co-treatment with PD-123319 in the CGP/PD group. The gene expression of renin was significantly increased in the kidneys in the CGP and CGP/PD groups, suggesting that CGP-48933 had increased Ang II generation in those groups. In conclusion, counter-activation of AT(2)R by increased Ang II under AT(1)R blockade likely conferred an anti-fibrotic protection in this model.

Angiotensin II↗