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Biomedical subjects

Takashi Taguchi

Publications and source records attributed to Takashi Taguchi.

At least 19 recordsLinked to original sources
PubMed2006

The collagen-specific molecular chaperone HSP47: is there a role in fibrosis?

Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that is required for molecular maturation of various types of collagens. Recent studies have shown a close association between increased expression of HSP47 and excessive accumulation of collagens in scar tissues of various human and experimental fibrotic diseases. It is presumed that the increased levels of HSP47 in fibrotic diseases assist in excessive assembly and intracellular processing of procollagen molecules and, thereby, contribute to the formation of fibrotic lesions. Studies have also shown that suppression of HSP47 expression can reduce accumulation of collagens to delay the progression of fibrotic diseases in experimental animal models. Because HSP47 is a specific chaperone for collagen synthesis, it provides a selective target to manipulate collagen production, a phenomenon that might have enormous clinical impact in controlling a wide range of fibrotic diseases. Here, we outline the fibrogenic role of HSP47 and discuss the potential usefulness of HSP47 as an anti-fibrotic therapeutic target.

Animals↗
PubMed2006

Life-long suppression of growth hormone-insulin-like growth factor I activity in genetically altered rats could prevent age-related renal damage.

To determine whether life-long reduction in the GH/IGF-I activity could be renoprotective and attenuate renal damage, we examined the kidneys of transgenic strain of rats whose GH gene was suppressed by an antisense GH transgene. Male rats homozygote for the transgene (tg/tg) had a reduced number of pituitary GH-secreting cells, and 53% less plasma concentration of IGF-I, compared with wild-type (wt/wt) rats at 6 months of age. We compared the kidneys obtained from male wild-type young (6 months) and old (24 months) rats with male homozygote transgenic young (6 months) and old (24 months) rats. The wild-type rats showed features of renal damage as they grew older, including glomerulosclerosis (higher sclerosis index at 24 months; P<0.0001), tubulointerstitial widening (increased interstitial volume at 24 months; P<0.0001), and presence of phenotypically altered myofibroblasts and increased accumulation of collagens. Life-long suppression of GH/IGF-I activity resulted in prevention of age-associated renal diseases in homozygote transgenic rats at 24 months (sclerosis index: 1.65+/-0.11 in wild-type vs. 0.463+/-0.061 in transgenic rats; interstitial volume: 34.2+/-0.82 in wild-type vs. 12.8+/-0.32 in homozygote transgenic rats at 24 months; P<0.0001). Such reno-protective effects in transgenic rats were associated with decreased renal accumulation of ED-1-positive macrophages, and less renal expression of pro-fibrogenic factors, including connective tissue growth factor and heat shock protein 47. Our in vivo genetic manipulation study provides direct evidence of reno-protective effects of life-long suppression of GH/IGF-I system, by reducing renal infiltration of inflammatory cells, and by suppressing the synthesis of profibrogenic factors and accumulation of extracellular matrix protein.

Actins↗
PubMed2006

Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process.

Fibroblast growth factor 23 null mice (Fgf-23-/-) have a short lifespan and show numerous biochemical and morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, and atrophy of the intestinal villi, skin, thymus, and spleen. Furthermore, increased vitamin D activities in homozygous mutants are associated with severe atherosclerosis and widespread soft tissue calcifications; ablation of vitamin D activity from Fgf-23-/- mice, by genetically deleting the 1alpha(OH)ase gene, eliminates atherosclerosis and ectopic calcifications and significantly rescues premature aging-like features of Fgf-23-/- mice, resulting in prolonged survival of Fgf-23-/-/1alpha(OH)ase-/- double mutants. Our results indicate a novel role of Fgf-23 in developing premature aging-like features through regulating vitamin D homeostasis. Finally, our data support a new model of interactions among Fgf-23, vitamin D, and klotho, a gene described as being associated with premature aging process.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗
PubMed2006

Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy.

BACKGROUND: We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers (ARB). METHODS: We examine the role of aldosterone breakthrough in 43 normotensive, proteinuric (0.7 +/- 0.3 g/day) outpatients (aged 41.5 +/- 10.9 years) with immunoglobulin A nephropathy (IgAN) accompanied by stable renal function (creatinine clearance >50 mL/min). The patients were treated with temocapril (1 mg; n = 14), losartan (12.5 mg; n = 16), or a combination therapy (n = 13) for 12 months. We prospectively evaluated blood pressure (BP), urinary protein excretion (UPE), biochemical parameters and the renin-angiotensin-aldosterone system before and after 12 months of treatment. RESULTS: Although the overall plasma aldosterone concentrations values did not change after any of the treatments administered for 12 months, they eventually increased in 23 (temocapril, seven patients; losartan, eight patients; combination, seven patients) of the 43 patients (53.4%; aldosterone breakthrough), and fell in the remainder (46.6%). Blood pressure and renal function did not differ among the three groups at 12 months. In contrast, UPE was significantly higher in patients with, than without aldosterone breakthrough during temocapril and losartan administration. However, combination therapy induced a more remarkable reduction in UPE regardless of aldosterone breakthrough. CONCLUSIONS: A combination of ACE inhibitors and ARB in normotensive patients with IgAN produces a more profound decrease in proteinuria than either monotherapy. This additive antiproteinuric effect is not dependent on aldosterone breakthrough. Additional larger, prospective, randomized studies will be needed for general acceptance of this strategy.

Adult↗
PubMed2006

Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals.

Fibroblast growth factor-23 (FGF-23) is one of the circulating phosphaturic factors associated with renal phosphate wasting. Fgf-23-/- animals show extremely high serum levels of phosphate and 1,25-dihydroxyvitamin D3, along with abnormal bone mineralization and soft tissue calcifications. To determine the role of vitamin D in mediating altered phosphate homeostasis and skeletogenesis in the Fgf-23-/- mice, we generated mice lacking both the Fgf-23 and 1alpha-hydroxylase genes (Fgf-23-/-/1alpha(OH)ase-/-). In the current study, we have identified the cellular source of Fgf-23 in adult mice. In addition, loss of vitamin D activities from Fgf-23-/- mice reverses the severe hyperphosphatemia to hypophosphatemia, attributable to increased urinary phosphate wasting in Fgf-23-/-/1alpha(OH)ase-/- mice, possibly as a consequence of decreased expression of NaPi2a. Ablation of vitamin D from Fgf-23-/- mice resulted in further reduction of total bone mineral content and bone mineral density and reversed ectopic calcification of skeleton and soft tissues, suggesting that abnormal mineral ion homeostasis and impaired skeletogenesis in Fgf-23-/- mice are mediated through enhanced vitamin D activities. In conclusion, using genetic manipulation studies, we have provided evidence for an in vivo inverse correlation between Fgf-23 and vitamin D activities and for the severe skeletal and soft tissue abnormalities of Fgf-23-/- mice being mediated through vitamin D.

Animals↗
PubMed2005

Cyclic and characteristic expression of phosphorylated Akt in human endometrium and decidual cells in vivo and in vitro.

BACKGROUND: Akt is activated by phosphorylation and plays an important role in cell survival and maintenance of structure. METHODS: We investigated whether phosphorylated Akt was characteristically expressed in human endometrium in vivo and whether insulin-like growth factor-I (IGF-I) can activate Akt using cultured decidualized human stromal cells in vitro, using immunohistochemistry and Western blotting analysis. RESULTS: The levels of phosphorylated Akt protein increased markedly in the decidual tissues from ectopic pregnancy. The expression of phosphorylated Akt protein in stromal cells increased with the decidualization. The decidual cells showed strong cytoplasmic staining for phosphorylated Akt. However, cultured decidualized human stromal cells diminished phosphorylated Akt expression compared to control cells. IGF-I administration to decidualized human stromal cells significantly recovered pAkt expression. The effect of IGF-I on decidualized human stromal cells was blocked by an inhibitor of phosphatidylinositol-3 kinase (PI3K) (LY294,002). These results suggest that IGF-I may activate Akt via PI3K in human endometrium and decidua. The expression of phosphorylated Akt in stromal cells was only detected in the functional layer, where tissue remodelling occurs during menstruation or implantation. CONCLUSIONS: Akt activation may be involved in cell survival and extracellular matrix remodelling in human endometrium and decidua.

Chromones↗
PubMed2005

Expression of matrix metalloproteinase-9 associated with ets-1 proto-oncogene in rat tubulointerstitial cells.

BACKGROUND: Ets-1 proto-oncogene exhibits multiple activities in the transcriptional regulation of numerous genes including metalloproteinase (MMP)-1, -3 and -9. MMPs play an important role in the remodelling of extracellular matrix in various renal diseases. However, the role of the Ets-1-MMP axis in advanced renal diseases is uncertain. In the present study, we investigated whether Ets-1 is involved in interleukin (IL)-1-mediated expression of MMPs in tubulointerstitial cells. METHODS: Rat renal fibroblasts (NRK-49F) and tubular epithelial cells (NRK-52E) were cultured and allocated to an IL-1beta-treated group (10 ng/ml), a platelet-derived growth factor (PDGF)-BB-treated group (25 ng/ml) and a control group. Protein and mRNA were extracted after 1, 6, 12 and 24 h of treatment. Parallel flasks were treated with 2 muM ets-1 antisense oligodeoxynucleotides (ODNs) before exposure to IL-1beta. The expression of Ets-1 protein was evaluated by western blotting. The activities of MMPs were evaluated by gelatin zymography. The expression of ets-1 and/or MMP-9 mRNA was evaluated semiquantitatively by real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In NRK-49F cells, Ets-1 protein increased significantly by 6.8-fold at 6 h, and MMP-9 activity increased significantly by 9.9-fold at 12 h in the IL-1beta-treated group compared with controls. MMP-2 and -3 activities also increased significantly in the IL-1beta-treated group. In NRK-52E cells, Ets-1 protein was 3.1 times higher at 1 h, and the latent form of MMP-9 activity increased 3.4-fold at 6 h in the IL-1beta group compared with controls. However, MMP-2 or MMP-3 activities were not markedly altered by IL-1beta treatment compared with controls. When the cells were treated with ets-1 antisense ODNs before IL-1beta treatment, Ets-1 protein expression decreased at least 50%, and MMP-9 activity was clearly inhibited in both cells. We also confirmed that MMP-9 activity was upregulated on days 21 and 28 in renal cortex of rat crescentic glomerulonephritis. CONCLUSIONS: The Ets-1 transcriptional factor may participate in IL-1beta-mediated MMP-9 expression in tubulointerstitial cells.

Animals↗
PubMed2005

Nephronophthisis in two siblings.

We describe here two sisters with nephronophthisis, which was not detected until the development of endstage renal failure. Twenty- and 15-year-old female siblings were admitted to our hospital for further examination of renal dysfunction. No urinalysis abnormalities had been found in yearly health checks in either patient. The serum creatinine level was 7.2 mg/dl in case 1 (the 20-year-old) and 6.4 mg/dl in case 2. Medical history, physical findings, and laboratory tests showed no evidence of urinary tract infection, use of any drugs, arthritis, or skin eruptions. To identify the cause of the renal failure, open left renal biopsies were performed in both patients. Histopathological findings were very similar in the two patients and included marked tubular and interstitial changes (tubular dilatation, focal tubular atrophy, interstitial fibrosis, and infiltration of mononuclear cells). The glomeruli were devoid of mesangial proliferation, mesangial expansion, and adhesion of Bowman's capsule. Based on the clinical and pathological findings, the final diagnosis was nephronophthisis in both patients. It is important to remember that some progressive renal diseases, including nephronophthisis, cannot be detected even by annual urinary screening tests, which are widely performed in Japan.

Adolescent↗
PubMed2005

Interstitial expression of heat-shock protein 47 correlates with capillary deposition of complement split product C4d in chronic allograft nephropathy.

BACKGROUND: Chronic allograft nephropathy (CAN), associated with late-allograft dysfunction is caused by alloantigen-dependent and -independent mechanisms, and eventually leads to interstitial fibrosis (ci). Activation of complement cascade is considered to be a poor prognostic marker of graft survival. This study was designed to examine the relationship between the expression of C4d and heat-shock protein 47 (HSP47, a collagen-specific chaperone) in the development of interstitial fibroproliferative lesions in CAN. METHODS: Sixty-three renal allograft biopsy specimens, obtained from 48 patients, were examined for the expression of C4d, HSP47, CD68 and alpha-smooth muscle actin (alpha-SMA) by immunohistochemistry. Double-staining was performed to determine the colocalization of C4d and HSP47. The relationship of between the expression of C4d, HSP47, CD68 and alpha-SMA and the clinical and histopathological parameters were statistically analysed. RESULTS: No expression of C4d was noted in the tubulointerstitium including peritubular capillary (PTC) of the control kidney. C4d was expressed in PTC in one-third of allograft renal tissues with morphological evidences of CAN. The interstitial cells around the fibrotic areas of the PTC of CAN were positive for the expression of HSP47. The deposition of C4d in PTC correlated with interstitial expression of HSP47 around the PTC. Most HSP47 expressing cells were phenotypically altered myofibroblasts, as determined by the dual staining of alpha-SMA. CONCLUSIONS: The increased expression of HSP47 positively correlated with the expression of C4d in PTC, and might contribute to the progression of interstitial ci in CAN.

Adolescent↗
PubMed2005

Involvement of stress proteins in renal diseases.

Heat shock proteins (HSPs) are a distinctive class of proteins that have evolved to cope with stress to provide cellular defence against a wide range of cell injuries. HSPs play an important role in the assembly and folding of intracellular polypeptides, and help in restoring the biological activities of abnormal proteins. Cellular stress responses include a transient rearrangement of functional activities, in order to protect and maintain essential cellular functions, possibly by inducing HSPs. HSPs help in restoring protein homeostasis and assist in cellular recovery from stress, either by repairing damaged proteins through refolding or by degrading them. Recent studies have documented the important roles of stress proteins in renal cell survival and matrix remodeling in a number of acute and chronic renal diseases. This brief review summarizes some of the important aspects of HSPs and their relevance to various renal diseases.

Animals↗
PubMed2005

Heat shock protein 47 and renal fibrogenesis.

Recent research has greatly increased our knowledge regarding the molecular mechanisms of collagen synthesis and processing. Heat specific shock protein (HSP47) is a collagen-specific molecular chaperone, and helps in post-translational modifications of procollagens, during biosynthesis of collagen. Both in vivo and in vitro studies have convincingly demonstrated that HSP47 is localized in the endoplasmic reticulum of collagen-producing cells, and that its synthesis is closely associated with the rate of procollagen assembly. Recent studies are directed towards the pathological relevance of HSP47 in tissue scarring, a process that is characterized by excessive accumulation of collagens. It appears likely that increased levels of HSP47 in fibrotic diseases assist in increased assembly of procollagen, and thereby help in excessive accumulation of collagens in the fibrotic mass. Such profibrotic effects of HSP47 suggest that modulation of HSP47 expression in scarring diseases might alter the course of fibrotic diseases. In this brief article, we review the role of HSP47 in renal fibrotic diseases and its relevance to other scarring diseases.

Animals↗
PubMed2005

Cisplatin-associated nephrotoxicity and pathological events.

Cisplatin (cis-diamminedichloroplatinum(II)) is an effective chemotherapeutic agent, and is successfully used in the treatment of a wide range of tumors. Despite its effectiveness as an anti-tumor drug, nephrotoxic side effects have significantly restricted its clinical use. Tubular epithelial cell deletion following cisplatin treatment is a major cause of renal injury. Oxidative stress significantly contributes to cisplatin-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of cisplatin. The renal microenvironmental changes following cisplatin treatment is a complex process and could be broadly categorized into three main pathological events, which at times might overlap: initial cytotoxic events, inflammatory events and fibroproliferative events. Stress responses and heat shock proteins generated following cisplatin treatment are actively involved in the initiation and progression of these events. In this article, we will briefly summarize factors involved in various phases of cisplatin-induced renal injuries.

Antineoplastic Agents↗
PubMed2005

Oxidant stress in renal pathophysiology.

Despite recent progress in identifying a number of important factors that may play central roles in various renal diseases, the precise molecular basis of renal injuries remains unclear. Recent studies have documented an important role for oxidant stress in several renal diseases. Oxidant stress by overproduction of reactive oxygen species, generation of reactive nitrogen species, and/or modulation of cellular antioxidant enzyme activities, resulting in the activation of certain transcription factors, and synthesis and/or release of inflammatory cytokines, chemokines, growth factors, and extracellular matrix proteins. These changes alter the balance in the microenvironment of the kidney, and may activate signaling cascades that induce and propagate renal injury. Complex molecular interactions and cross-talk between the activated signaling pathways, in turn, define the nature and clinical course of the disease process. In this article, we will briefly present the relevance of the oxidant stress in the pathogenesis of various renal diseases.

Animals↗
PubMed2004

Nuclear trafficking of macromolecules by an oligopeptide derived from Vpr of human immunodeficiency virus type-1.

Vpr, an accessory gene product of HIV-1, is incorporated into cells when added to the culture medium. Via such function Vpr has been shown to transduce a protein into cells that is expressed as a chimeric protein with Vpr. The domain required for protein transduction, however, remained to be clarified. Here we identified a sequence encompassing 52-78 amino acids of Vpr (C45D18) that enables nuclear trafficking of proteins. When chemically synthesized C45D18 was added to the culture medium of human cord blood mononuclear (CBMN) cells, most cells became positive for the incorporated C45D18. Furthermore, recombinant proteins conjugated with the C45D18 were efficiently transduced and transported to regions corresponding to the nucleus. Incorporation of C45D18-conjugated protein was observed within a few hours after addition of the protein, independent of cellular growth. Although it is well known that Tat-derived peptide has a transducing activity, C45D18 was more active than Tat peptide for trafficking proteins into cells. Taking together with results from FACS analysis revealing that more than 90% of CBMN cells were positive for X-gal staining after treatment of C45D18-conjugated beta-galactosidase, we propose that C45D18 translocates bioactive macromolecules directly into the nucleus.

Active Transport, Cell Nucleus↗
PubMed2004

A solitary Peutz-Jeghers-type hamartomatous polyp in the duodenum. A case report including results of mutation analysis.

BACKGROUND/AIMS: We report a case of solitary Peutz-Jeghers-type hamartomatous polyp of the duodenum in a 22-year-old Japanese woman along with the results of genomic analysis. METHODS/RESULTS: The patient was almost asymptomatic, though endoscopic examination revealed a solitary lobular polypoid lesion measuring 3 cm in diameter in the first portion of the duodenum. The lesion was resected endoscopically. Histopathological examination showed hyperplasia with a tree branch-like extension of the lamina propria derived from the muscularis mucosae, consistent with histological features of polyps of Peutz-Jeghers syndrome (PJS). No mucocutaneous pigmentation of the skin was evident and family history was negative. Analysis of the loss of heterozygosity at the locus of 19p 13.3 and mutation analysis of the STK11/LKB1 gene, which has recently been recognized as a susceptible gene in PJS, were performed. However, no evidence of genomic abnormality was found. CONCLUSION: The clinical and investigative findings in our case suggest that the solitary Peutz- Jeghers-type hamartomatous polyp can be regarded as a clinical entity separate from PJS.

Adult↗
PubMed2004

Immunoinflammatory responses and fibrogenesis.

In response to injury, tissues adjacent to the damaged area initiate a cascade of inflammatory and matrix remodeling events that are necessary to restore tissue integrity and function. The typical features of such healing effects in adult mammals are deposition of matrix proteins, which mature to scar tissues. In general, the wound healing response demonstrates certain commonalities across organs, but there are also organ-specific mechanisms. Such organ-specific controlled healing and uncontrolled tissue scarring are partly determined by the bioactivities of resident cells and local microenvironments, which are influenced by multiple factors, including the presence of specific types of cytokines (Th1 and Th2), chemokines, growth factors, cell-cell interaction, and reorganization of matrix proteins. In this article, we briefly present the relevance of Th1 and Th2 responses and the significance of interactions between matrix-producing cells and inflammatory cells during granuloma tissue and scar tissue formation.

Animals↗