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Masakazu Haneda

Publications and source records attributed to Masakazu Haneda.

At least 55 records · Page 3Linked to original sources
PubMed2003

Involvement of ERK pathway in albumin-induced MCP-1 expression in mouse proximal tubular cells.

Persistent proteinuria has been indicated to be a major risk factor for the development of tubulointerstitial damage through a process of proinflammatory molecule expression. Monocyte chemoattractant protein-1 (MCP-1) was shown to contribute to recruitment of immune cells into the renal interstitium in acute and chronic renal diseases. However, the molecular mechanisms by which proteinuria causes MCP-1 expression in proximal tubular cells have not been fully clarified. In this study, we examined whether albumin overload-induced MCP-1 expression was regulated by mitogen-activated protein kinase (MAPK) in mouse proximal tubular (mProx) cells. Exposure of mProx cells to delipidated bovine serum albumin (BSA) induced mRNA and protein expression of MCP-1 in a time- and dose-dependent manner. BSA activated extracellular signal-regulated kinase (ERK1/2) and p38 MAPK. The MEK inhibitor U-0126 partially suppressed BSA-induced MCP-1 expression and MCP-1 promoter/luciferase reporter activity. U-0126 also inhibited an increase in nuclear factor-kappaB and activator protein-1 DNA-binding activity of MCP-1 promoter by protein overload in mProx cells. In addition, we found that U-0126 inhibited BSA-induced nuclear factor-kappaB reporter activity and inhibitory protein degradation in mProx cells. In conclusion, these findings indicate that ERK signaling is involved in BSA-induced MCP-1 expression in mProx cells.

Animals↗
PubMed2003

C-106T polymorphism of AKR1B1 is associated with diabetic nephropathy and erythrocyte aldose reductase content in Japanese subjects with type 2 diabetes mellitus.

BACKGROUND: The C-106T polymorphism of AKR1B1, which encodes aldose reductase (AR), was reported to be associated with diabetic nephropathy (DN). However, this association in Japanese patients with type 2 diabetes mellitus and its potential role as a clinical marker remain unclear. METHODS: The C-106T polymorphism was genotyped in 228 cases (microalbuminuria or overt proteinuria) and 220 controls (normoalbuminuria with diabetes duration > or =10 years) for a case-control comparison, and the association with erythrocyte AR content was investigated. In addition, a new C-11G polymorphism in the promoter region of AKR1B1 was genotyped. RESULTS: The distribution of genotypes of the C-106T polymorphism in cases was significantly different from that in controls (P = 0.031). Carriers of the TT genotype at the C-106T polymorphism were more frequent in cases than controls, with an odds ratio of 4.7 (95% confidence interval, 1.3 to 17). Erythrocyte AR content was significantly elevated in TT carriers in comparison to non-TT carriers (13.1 +/- 1.2 versus 10.2 +/- 1.2 ng/mg hemoglobin [Hb]; P < 0.001) and in cases in comparison to controls (10.6 +/- 1.3 versus 10.1 +/- 1.2 ng/mg Hb; P = 0.041). However, distribution of genotypes of the C-11G polymorphism and estimated frequencies of haplotypes defined by these 2 polymorphisms did not differ between cases and controls. CONCLUSION: The TT genotype of the C-106T polymorphism of AKR1B1 increases the risk for DN in Japanese subjects with type 2 diabetes mellitus, which could be linked in part to greater expression of AR.

Aged↗
PubMed2003

Activation of Src kinase in platelet-derived growth factor-B-dependent tubular regeneration after acute ischemic renal injury.

We previously reported that the platelet-derived growth factor B-chain (PDGF-B)/PDGF receptor (PDGFR) axis is involved in tubular regeneration after ischemia/reperfusion injury of the kidney. In the present study, we examined the activation of Src tyrosine kinase, a crucially important signaling molecule for PDGFR, and assessed the role of Src in PDGF-B-dependent renal tubular regeneration afterischemia/reperfusion injury. Immunoblot using clone 28, a monoclonal antibody specific for the active form of Src kinases, demonstrated increased active Src expression in the injured rat kidney 6 hours after reperfusion with peak activation at 12 hours. In vitro kinase assay confirmed increased Src activity that concurred with PDGFR-beta activation as detected by the increment of receptor-phosphorylated tyrosine. Immunohistochemistry using clone 28 demonstrated that active Src was preferentially expressed in the S3 segment of the proximal tubule in reperfused kidney, where it is not normally expressed. This enhanced expression of active Src was co-localized with the increased PDGFR expression in the tubular cells that were undergoing cell proliferation cycle. Trapidil administration suppressed Src and PDGFR-beta activation in the reperfused kidney and resulted in deteriorated renal function. These findings suggest that active Src participates in PDGF-B-dependent regeneration of tubular cells from acute ischemic injury.

Animals↗
PubMed2003

Diabetic neuropathy and nerve regeneration.

Diabetic neuropathy is the most common peripheral neuropathy in western countries. Although every effort has been made to clarify the pathogenic mechanism of diabetic neuropathy, thereby devising its ideal therapeutic drugs, neither convinced hypotheses nor unequivocally effective drugs have been established. In view of the pathologic basis for the treatment of diabetic neuropathy, it is important to enhance nerve regeneration as well as prevent nerve degeneration. Nerve regeneration or sprouting in diabetes may occur not only in the nerve trunk but also in the dermis and around dorsal root ganglion neurons, thereby being implicated in the generation of pain sensation. Thus, inadequate nerve regeneration unequivocally contributes to the pathophysiologic mechanism of diabetic neuropathy. In this context, the research on nerve regeneration in diabetes should be more accelerated. Indeed, nerve regenerative capacity has been shown to be decreased in diabetic patients as well as in diabetic animals. Disturbed nerve regeneration in diabetes has been ascribed at least in part to all or some of decreased levels of neurotrophic factors, decreased expression of their receptors, altered cellular signal pathways and/or abnormal expression of cell adhesion molecules, although the mechanisms of their changes remain almost unclear. In addition to their steady-state changes in diabetes, nerve injury induces injury-specific changes in individual neurotrophic factors, their receptors and their intracellular signal pathways, which are closely linked with altered neuronal function, varying from neuronal survival and neurite extension/nerve regeneration to apoptosis. Although it is essential to clarify those changes for understanding the mechanism of disturbed nerve regeneration in diabetes, very few data are now available. Rationally accepted replacement therapy with neurotrophic factors has not provided any success in treating diabetic neuropathy. Aside from adverse effects of those factors, more rigorous consideration for their delivery system may be needed for any possible success. Although conventional therapeutic drugs like aldose reductase (AR) inhibitors and vasodilators have been shown to enhance nerve regeneration, their efficacy should be strictly evaluated with respect to nerve regenerative capacity. For this purpose, especially clinically, skin biopsy, by which cutaneous nerve pathology including nerve regeneration can be morphometrically evaluated, might be a safe and useful examination.

Animals↗
PubMed2003

Braille alexia during visual hallucination in a blind man with selective calcarine atrophy.

The case of a 56-year-old man who has been blind for 25 years due to retinal degeneration is herein described. The patient complained of elementary visual hallucination, during which it was difficult for him to read Braille. Brain magnetic resonance imaging showed marked atrophy of the bilateral striate cortex. Visual hallucination as a release phenomenon of the primary visual cortex has never been reported to cause alexia for Braille. The present case supports the results of recent functional imaging studies of the recruitment of striate and prestriate cortex for Braille reading.

Atrophy↗
PubMed2003

Progression of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy, a kidney disease caused by diabetes, is the most devastating and money-consuming complication in patients with diabetes throughout the world. The cardinal lesion of diabetic nephropathy resides in renal glomeruli and is called diabetic glomerulosclerosis. Hyperglycemia is responsible for the development and progression of diabetic nephropathy through metabolic derangements, including increased oxidative stress, renal polyol formation, activation of protein kinase C (PKC)-mitogen-activated protein kinases (MAPKs), and accumulation of advanced glycation end products, as well as such hemodynamic factors as systemic hypertension and increased intraglomerular pressure. METHODS: We examined whether inhibition of the PKC-MAPK pathway could inhibit functional and pathological abnormalities in glomeruli from diabetic animal models and cultured mesangial cells exposed to high glucose condition and/or mechanical stretch. RESULTS: Direct inhibition of PKC by PKC beta inhibitor prevented albuminuria and mesangial expansion in db/db mice, a model of type 2 diabetes. We also found that inhibition of MAPK by PD98059, an inhibitor of MAPK, or mitogen-activated extracellular regulated protein kinase kinase prevented enhancement of activated protein-1 (AP-1) DNA binding activity and fibronectin expression in cultured mesangial cells exposed to mechanical stretch in an in vivo model of glomerular hypertension. CONCLUSION: These findings highlight the important role of PKC-MAPK pathway activation in mediating the development and progression of diabetic nephropathy.

Animals↗
PubMed2003

N-Acetyl-seryl-aspartyl-lysyl-proline inhibits TGF-beta-mediated plasminogen activator inhibitor-1 expression via inhibition of Smad pathway in human mesangial cells.

Recent large clinical trials indicate that angiotensin-converting enzyme inhibitors (ACE-I) attenuate the detrimental outcome of progressive renal disease. The hemoregulatory tetrapeptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP, AcSDKP) is hydrolyzed by ACE, and plasma Ac-SDKP level is increased by fivefold after treatment with ACE-I. Ac-SDKP was found to ameliorate cardiac and renal fibrosis in hypertensive animal models. However, the molecular mechanisms by which Ac-SDKP mediates anti-fibrotic effects remain unclear. This study is an examination of the interaction between Ac-SDKP and transforming growth factor-beta (TGF-beta), one of the key cytokines in the progression of renal disease, in human mesangial cells. Ac-SDKP inhibited TGF-beta1-induced plasminogen activator inhibitor-1 (PAI-1) and alpha2 (I) collagen mRNA. Ac-SDKP suppressed not only TGF-beta1-induced Smad2 phosphorylation at Ser-465/467 in a dose-dependent manner, but also the nuclear accumulation of receptor-regulated Smads (R-Smad), Smad2 and Smad3. As expected, Ac-SDKP inhibited TGF-beta-responsive Smad-dependent luciferase reporters, 3TP-luc and 4xSBE-luc. Immunofluorescence analysis revealed that the inhibitory Smad, Smad7, was exported to the cytoplasm from the nucleus by the treatment with Ac-SDKP. These findings provide novel evidence that Ac-SDKP inhibits TGF-beta signal transduction through the suppression of R-Smad activation via nuclear export of Smad7, highlighting an alternative mechanism involved in the reno-protective efficacy of ACE-I.

Cell Culture Techniques↗
PubMed2003

Identification of a common risk haplotype for diabetic nephropathy at the protein kinase C-beta1 (PRKCB1) gene locus.

Abnormal activation of protein kinase C-beta isoforms in the diabetic state has been implicated in the development of diabetic nephropathy. It is thus plausible that DNA sequence differences in the protein kinase C-beta1 gene (PRKCB1), which encodes both betaI and betaII isoforms, may influence susceptibility to nephropathy. Nine single-nucleotide polymorphisms (SNP) in PRKCB1 were tested for association with diabetic nephropathy in type I diabetes mellitus, by using both case-control and family-study designs. Allele and genotype distributions of two SNP in the promoter (--1504C/T and --546C/G) differed significantly between case patients and control patients (P < 0.05). These associations were particularly strong with diabetes mellitus duration of <24 yr (P = 0.002). The risk of diabetic nephropathy was higher among carriers of the T allele of the --1504C/T SNP, compared with noncarriers (odds ratio, 2.54; 95% confidence interval, 1.39 to 4.62), and among carriers of the G allele of the --546C/G SNP (odds ratio, 2.45; 95% confidence interval, 1.37 to 4.38). Among individuals with diabetes mellitus duration of >/==" BORDER="0">24 yr, these two SNP were not associated with diabetic nephropathy. These positive findings were confirmed by using the family-based transmission disequilibrium test. The T-G haplotype, with both risk alleles, was transmitted more frequently than expected from heterozygous parents to offspring who developed diabetic nephropathy during the first 24 yr of diabetes mellitus. It is concluded that DNA sequence differences in the promoter of PRKCB1 contribute to diabetic nephropathy susceptibility in type I diabetes mellitus.

Adult↗
PubMed2003

Effects of antioxidants in diabetes-induced oxidative stress in the glomeruli of diabetic rats.

Numerous reports have demonstrated that oxidative stress induced by diabetes plays an important role in the development and progression of diabetic vascular complications including nephropathy. Indeed, there is emerging evidence that the formation of reactive oxygen species (ROS) is a direct consequence of hyperglycemia. Biomarkers for oxidative damage to DNA, lipids, and proteins are also supporting the concept of increased oxidative stress in diabetes and diabetic nephropathy. However, there is an unanswered question: When does oxidative stress as a pathogenetic event occur in the process of diabetic nephropathy? To answer this question, glomerular ROS was imaged with the use of 2', 7'-dichlorofluorescein diacetate (DCFH-DA). The image of DCF fluorescence was strong in glomeruli from diabetic rats as compared with that of glomeruli from nondiabetic control rats. mRNA expression of antioxidant enzymes such as catalase, glutathione peroxidase, Cu/Zn superoxide dismutase, and heme oxygenase-1 (HO-1) was also determined because oxidative stress definitely refers to the situation of an imbalance between the production of ROS and antioxidant defense. The mRNA expression of catalase, glutathione peroxidase, and Cu/Zn superoxide dismutase 2 wk after the induction of diabetes was not significantly different from that in control rats. Alternatively, mRNA and protein expression of HO-1 was strongly induced by 16-fold in diabetic glomeruli after the induction of diabetes. Antioxidant treatment with either vitamin E or probucol almost completely normalized HO-1 overexpression in diabetic glomeruli, supporting the existence of oxidative stress in the glomeruli of early diabetes. Furthermore, It has reported that antioxidant treatment with vitamin E, probucol, alpha-lipoic acid, or taurine normalized diabetes-induced not only renal dysfunction such as albuminuria and glomerular hypertension but also glomerular pathologies. In summary, oxidative stress by diabetes could play a crucial role in the development and progression of diabetic nephropathy, and antioxidant treatment could be a potential therapeutic procedure for diabetic nephropathy.

Animals↗
PubMed2003

Translocation of glomerular p47phox and p67phox by protein kinase C-beta activation is required for oxidative stress in diabetic nephropathy.

Oxidative stress is implicated to play an important role in the development of diabetic vascular complications, including diabetic nephropathy. It is unclear whether oxidative stress is primarily enhanced in the diabetic glomeruli or whether it is merely a consequence of diabetes-induced glomerular injury. To address this issue, we examined diabetic glomeruli to determine whether oxidative stress is enhanced, as well as examined the role of protein kinase C (PKC)-beta activation in modulating NADPH oxidase activity. Urinary 8-hydroxydeoxyguanosine excretion and its intense immune-reactive staining in the glomeruli were markedly higher in diabetic than in control rats, and these alterations were ameliorated by a treatment with a selective PKC-beta inhibitor, ruboxistaurin (RBX; LY333531) mesylate, without affecting glycemia. NADPH oxidase activity, which was significantly enhanced in diabetic glomeruli and the source of reactive oxygen species (ROS) generation, was also improved by RBX treatment by preventing the membranous translocation of p47phox and p67phox from cytoplasmic fraction without affecting their protein levels. Adenoviral-mediated PKC-beta(2) overexpression enhanced ROS generation by modulating the membranous translocation of p47phox and p67phox in cultured mesangial cells. We now demonstrate that oxidative stress is primarily enhanced in the diabetic glomeruli due to a PKC-beta-dependent activation of NADPH oxidase resulting in ROS generation.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Association of solute carrier family 12 (sodium/chloride) member 3 with diabetic nephropathy, identified by genome-wide analyses of single nucleotide polymorphisms.

To identify genetic elements that might confer susceptibility to diabetic nephropathy, we performed a genome-wide analysis of gene-based single nucleotide polymorphisms (SNPs) in a large cohort of Japanese patients with diabetes. In case-control association studies, patients with type 2 diabetes were divided into two groups, one having retinopathy as well as overt nephropathy and the other (the control group) having diabetic retinopathy but with no signs of renal involvement. Genotyping of these patients at >55,000 SNP loci indicated a gene encoding solute carrier family 12 member 3 (SLC12A3) to be a good candidate for the susceptibility to diabetic nephropathy, in view of a significant association of one landmark SNP located in the 24th intron (chi(2) = 15.4, P = 0.000087, odds ratio = 2.53 [95% CI 1.57-4.09]). Subsequent analysis of additional genetic variations in this gene identified several SNPs that were significantly associated with nephropathy, especially one in exon 23 (+78 G to A: Arg913Gln, chi(2) = 18.5, P = 0.00002, odds ratio = 2.53 [95% CI 1.64-3.90]). The results implicated that substitution of Arg913 to Gln in the SLC12A3 gene might reduce the risk to develop diabetic nephropathy and suggested that the gene product might be a potential target for the prevention or treatment of this disease.

Age of Onset↗
PubMed2003

Prevalence and major risk factors of reduced flow volume in lower extremities with normal ankle-brachial index in Japanese patients with type 2 diabetes.

OBJECTIVE: To clarify the prevalence and major risk factors of reduced flow volume in lower extremities with normal ankle-brachial index (ABI) in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We recruited 208 consecutive type 2 diabetic patients and 33 age-matched nondiabetic subjects (control group) admitted to our hospital. Thirty-two of the patients had low ABI (<0.90) and intermittent claudication (peripheral arterial disease [PAD] group), and 176 patients had normal ABI (>0.9) (non-PAD group). We evaluated flow volume and resistive index, as an index of arterial resistance to blood flow, at the popliteal artery using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. RESULTS: Simple linear regression analysis showed a negative correlation between resistive index and total flow volume in the non-PAD group (r = -0.714, P < 0.001). We defined the means +/- 2 SD of these parameters in the control group as the normal range; abnormal resistive index was >1.017, and abnormal flow volume was <50.8 ml/min. The non-PAD group was divided according to the levels of these parameters: 80 patients had both normal resistive index and normal flow volume (normal group); of 96 patients with higher resistive index, 63 had normal flow volume (borderline group) and 33 had reduced flow volume (reduced group). Multiple regression analysis demonstrated that the major risk factors for reduced flow volume were age, hypertension, and diabetic nephropathy (r(2) = 0.303, P < 0.001). CONCLUSIONS: The prevalence of patients without PAD with reduced flow volume in the lower extremities was 16% (n = 33) and comparable with that of patients with PAD with intermittent claudication (n = 32), suggesting that increase in arterial resistance to blood flow may be one of the major causes of lower extremity arterial disease in Japan.

Aged↗
PubMed2003

APOE polymorphism and the progression of diabetic nephropathy in Japanese subjects with type 2 diabetes: results of a prospective observational follow-up study.

OBJECTIVE: The aim of this study is to clarify the conflicting results of the epsilon2/epsilon3/epsilon4 APOE polymorphism as a risk factor on diabetic nephropathy by a cohort study. RESEARCH DESIGN AND METHODS: A total of 429 Japanese subjects with type 2 diabetes and with normoalbuminuria (n = 299) or with microalbuminuria (n = 130) were enrolled in a prospective observational follow-up study during 1995-1998 and followed until 2001 (for at least 3 years). The endpoint was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy. RESULTS: During the study (the mean follow-up period: 4.4 +/- 1.0 years), 31 of 429 subjects progressed: 21 from normoalbuminuria to microalbuminuria and 10 from microalbuminuria to overt proteinuria. The allele frequency of the APOE polymorphism was significantly different between the progressors and the nonprogressors. Eight of 42 epsilon2 carriers (19%) progressed, whereas 23 of 387 noncarriers (6%) progressed with a relative risk of 3.2 (95% CI 1.5-6.7). When subjects were stratified by renal status at baseline, each relative risk for the progression in the epsilon2 carriers was 2.7 (0.99-7.4) in those with normoalbuminuria and 4.2 (1.3-13.3) in those with microalbuminuria. Furthermore, when analyzed only in subjects with normoalbuminuria and short duration of diabetes (<15 years) at baseline, the risk in the epsilon2 carriers became higher to 3.2 (1.2-8.8). CONCLUSIONS: Our follow-up study indicates that the epsilon2 allele of the APOE polymorphism is a prognostic risk factor for both the onset and the progression of diabetic nephropathy in Japanese type 2 diabetes.

Aged↗
PubMed2003

[Kidney and hypertension].

There is a unique relationship between the kidney and blood pressure. The importance of the kidney on the pathogenesis of hypertension was clearly demonstrated in renal transplantation studies both in genetic hypertensive rats and humans with hypertension. Also, hypertension accelerates loss of function of the diseased kidney and the antihypertensive treatment attenuates the progression of various renal diseases. A lot of mechanisms to explain this relationship are considered: salt retention, abnormalities of renal hemodynamics, inappropriate activation of the renin-angiotensin system etc. This review is an attempt to highlight a renal role on the development of hypertension, especially in diabetic nephropathy.

Animals↗
PubMed2002

Cyclic AMP inhibits stretch-induced overexpression of fibronectin in glomerular mesangial cells.

Glomerular hypertension is proposed to play an important role in the progression of various glomerular diseases. Glomerular mesangial cells are considered to be exposed to the stretch stress due to glomerular hypertension and are found to produce the excess amount of extracellular matrix (ECM) proteins including fibronectin when exposed to the mechanical stretch. Herein, we provide the evidence that cAMP-generating agents inhibit the stretch-induced overexpression of fibronectin through the inhibition of the stretch-induced activation of mitogen-activated protein kinases (MAPKs) in protein kinase-A-dependent manner. We also found that the mechanical stretch enhanced the binding of nuclear extracts to activator protein-1 (AP-1)-like sequences in the promoter region of rat fibronectin gene and this enhancement was also prevented by the cAMP-generating agent. These results indicate that the agents, which activate cAMP/protein kinase-A axis, may work protectively against the injury from glomerular hypertension in mesangial cells.

Animals↗
PubMed2002

15-Deoxy-Delta12,14-prostaglandin J2 inhibits IL-1beta-induced cyclooxygenase-2 expression in mesangial cells.

BACKGROUND: Cyclooxygenase-2 (COX-2), a key enzyme in the synthesis of prostaglandins, is induced in mesangial cells in response to proinflammatory cytokines. Recently, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2), one of the natural ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), has been reported to have an anti-inflammatory effect. Therefore, we examined the effect of 15d-PGJ2 on COX-2 expression in cultured rat mesangial cells. METHODS: Mesangial cells were incubated with 15d-PGJ2 for 30 minutes and then exposed to interleukin-1beta (IL-1beta). The expression of COX-2 mRNA and proteins was determined by Northern blot and immunoblot analyses, respectively. Accumulation of prostaglandin E2 (PGE2) was measured by an enzyme-linked immunosorbent assay (ELISA). Activities of mitogen-activated protein kinases (MAPKs) were evaluated by an immunoblot analysis. DNA binding activities of activator protein-1 (AP-1) or nuclear factor-kappaB (NF-kappaB) were examined by an electrophoretic mobility shift assay (EMSA). The activities of PPAR responsive elements (PPRE) and COX-2 promoter were measured by a luciferase reporter assay. RESULTS: 15D-PGJ2 significantly suppressed IL-1beta-induced COX-2 expression and PGE2 production, but thiazolidinediones, synthetic PPARgamma ligands, did not affect COX-2 expression. Moreover, the cells transfected with a PPRE luciferase reporter did not respond to 15d-PGJ2. IL-1beta rapidly activated extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), which were involved in the up-regulation of COX-2 induction, but 15d-PGJ2 inhibited the activation of these kinases. 15d-PGJ2 inhibited the IL-1beta-induced increase in binding activities of nuclear proteins to consensus AP-1 site and AP-1-like site of COX-2 promoter but not of NF-kappaB. IL-1beta was unable to activate the COX-2 promoter when the AP-1-like site was mutated. CONCLUSIONS: These data suggest that 15d-PGJ2 inhibits IL-1beta-induced COX-2 expression, independent of PPARgamma activation, by suppression of ERK and JNK pathways and AP-1 activation in mesangial cells. Thus, 15d-PGJ2 may play an important role in the negative feedback mechanism of COX-2 expression in renal inflammation and may be useful as an anti-inflammatory agent.

Animals↗