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1.
Cureus ; 14(6): e26087, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35747117

ABSTRACT

Airway narrowing due to trauma-induced retropharyngeal hematoma is rare. However, it is dangerous to overlook this lesion because it can lead to airway obstruction and even death. In this article, we report a case of a patient who developed pharyngeal pain and dysphagia two days after bruising on the forehead due to a fall and required intubation management. A 52-year-old man fell while walking and bruised his forehead two days before visiting our hospital. He had a sore throat and dysphagia two days after the injury and came to our hospital three days after the injury. The swelling was observed in the anterior neck, and stenotic sounds were heard in the upper airway. Cervical CT and MRI of the cervical spine showed extensive hyperabsorption areas in the ventral side of the cervical spine that appeared to be hematomas. No fracture of the cervical spine was observed. The patient has been placed on emergency tracheal intubation due to concerns about airway stenosis caused by the hematoma. Although pneumonia was observed during treatment, it resolved with antimicrobial therapy, and the hematoma tended to shrink, so the patient was extubated on the 15th day of admission. However, the patient was intubated again on the 17th day of hospitalization due to poor oxygenation. A tracheostomy was performed on the 26th day of hospitalization due to suspected narrowing of the upper airway caused by hematoma or sputum. On day 59 of hospitalization, the cannula was removed, and the patient was discharged home on the 68th day after hospitalization. Low-energy trauma tends to be underrecognized as producing anterior cervical hematomas that can lead to fatal airway narrowing. Care should be taken because fatal anterior cervical hematomas are not often part of the differential diagnosis due to their often delayed onset. More caution is needed if an underlying disease may cause coagulation abnormalities.

2.
J Diabetes Investig ; 13(4): 706-713, 2022 Apr.
Article in English | MEDLINE | ID: mdl-34743418

ABSTRACT

AIMS/INTRODUCTION: We aimed to replicate a new diabetes subclassification based on objective clinical information at admission in a diabetes educational inpatient program. We also assessed the educational outcomes for each cluster. METHODS: We included diabetes patients who participated in the educational inpatient program during 2009-2020 and had sufficient clinical information for the cluster analysis. We applied a data-driven clustering method proposed in a previous study and further evaluated the clinical characteristics of each cluster. We investigated the association between the clusters and changes in hemoglobin A1c level from the start of the education program. We also assessed the risk of re-admission for the educational program. RESULTS: We divided a total of 651 patients into five clusters. Their clinical characteristics followed the same pattern as in previous studies. The intercluster ranking of the cluster center coordinates showed strong correlation coefficients with those of the previous studies (mean ρ = 0.88). Patients classified as severe insulin-resistant diabetes (cluster 3) showed a more pronounced progression of renal dysfunction than patients classified as the other clusters. The patients classified as severe insulin-deficient diabetes (cluster 2) had the highest rate of reduction in hemoglobin A1c level from the start of the program (P < 0.01) and a tendency toward a lower risk of re-admission for the education program (hazard ratio 0.47, P = 0.09). CONCLUSION: We successfully replicated the diabetes subclassification using objective clinical information at admission for the education program. In addition, we showed that severe insulin-deficient diabetes patients tended to have better educational outcomes than patients classified as the other clusters.


Subject(s)
Diabetes Mellitus, Type 2 , Inpatients , Adult , Glycated Hemoglobin/analysis , Humans , Insulin , Japan/epidemiology
3.
Article in English | MEDLINE | ID: mdl-31743096

ABSTRACT

SUMMARY: Type B insulin resistance syndrome is characterized by the presence of autoantibodies to the insulin receptor. We present a 57-year-old male admitted to a hospital due to body weight loss of 16 kg and hyperglycemia of 13.6 mmol/L. He was diagnosed with type B insulin resistance syndrome because the anti-insulin receptor antibodies were positive. We informed him that some hyperglycemic cases of this syndrome had been reported to be spontaneously remitted in 5 years, and he did not agree to be treated with high-dose glucocorticoids and/or immunosuppressive agents due to his concern for their adverse effects such as hyperglycemia and immunosuppression. He chose to be treated with insulin and voglibose, but fair glucose control could not be obtained. Six years later, he agreed to be treated with low-dose glucocorticoids practicable in outpatient settings. One milligram per day of betamethasone was tried orally and reduced gradually according to the values of glycated hemoglobin. After 30 months of glucocorticoid treatment, the anti-insulin receptor antibodies became undetectable and his fasting plasma glucose and glycated hemoglobin were normalized. This case suggests that low-dose glucocorticoids could be a choice to treat type B insulin resistance syndrome in outpatient settings. LEARNING POINTS: Type B insulin resistance syndrome is an acquired autoimmune disease for insulin receptors. This case suggested the possibility of long-lasting, low-dose glucocorticoid therapy for the syndrome as an alternative for high-dose glucocorticoids or immunosuppressive agents. Since the prevalence of autoimmune nephritis is high in the syndrome, a delay of immunosuppressive therapy initiation might result in an exacerbation of nephropathy.

4.
Heliyon ; 5(6): e01817, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31206088

ABSTRACT

To obtain biocontrol agents for suppression of food-deteriorating fungi during storage of agricultural products, bacteria producing volatile organic compounds (VOCs) with strong antifungal activity were screened and isolated from various environmental samples. Among 136 bacterial isolates, strain TM-R showed the strongest and broadest antifungal activity. Based on physiological and genetical characterization, the bacterium was identified as Bacillus pumilus. The effects of VOCs produced by the bacterium, which was grown on four types of agar media (nutrient, Trypto-Soya, Luria-Bertani, and TM Enterprise), were examined against six species of fungi (Alternaria alternata, Aspergillus niger, Cladosporium cladosporioides, Curvularia lunata, Fusarium oxysporum, and Penicillium italicum) in both small- and large-scale tests (plate and 12-L tests, respectively). In the plate test, the bacterium markedly suppressed the mycelial growth of five fungi (Alternaria alternata, Cladosporium cladosporioides, Curvularia lunata, F. oxysporum, and P. italicum) but promoted the growth of Aspergillus niger. In the 12-L test, the degree of growth inhibitiondecreased; however, the bacterium grown on TMEA still exhibited the strongest inhibition, especially against P. italicum (growth inhibition rate of 93%). Surprisingly, the growth of Aspergillus niger was promoted even more strongly (-36%) by the bacterium on TMEA than in the plate test (-9%). Twenty-two of 32 VOCs detected by GC-MS were identified using three databases (NIST 2011, AromaOffice, and AroChemBase). The species and concentration of detected VOCs differed greatly among growth media. To identify causative antifungal VOCs, we estimated the correlation between growth inhibition of P. italicum by the bacterium grown on each of the four media vs. the relative abundance of individual VOCs. As a result, four VOCs (methyl isobutyl ketone, ethanol, 5-methyl-2-heptanone, and S-(-)-2-methylbutylamine) were determined to be the predominant antifungal VOCs. To the best of our knowledge, this study is the first to specify causative antifungal VOCs using such an approach.

6.
Gynecol Endocrinol ; 33(10): 819-821, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28490208

ABSTRACT

The kisspeptin is a neuropeptide to play physiological roles in regulating gonadotropin-releasing hormone secretion in the hypothalamus. In human plasma, the kisspeptin concentration is measured, but gonadotropin-releasing hormone is not. This study aims to understand the physiological roles of the circulating kisspeptin in lactational amenorrhea in humans because prolactin reduces the kisspeptin expression and luteinizing hormone secretion resulting in anovulations in rodent brains. Plasma kisspeptin levels were measured in 11 subjects in lactational amenorrhea and in four cases with pathological amenorrhea by different etiologies for comparison using the enzyme immunoassay specific for human kisspeptin. The plasma kisspeptin levels in the 11 women with lactational amenorrhea were 15.2 ± 2.5 fmol/mL (mean ± SD) which were not significantly different as compared with 16.5 ± 4.8 fmol/mL (mean ± SD) in four age-matched women with menstrual cycles as we reported previously. In the four cases with pathological amenorrhea, their plasma kisspeptin levels were from 5.8 to 13.7 fmol/mL. This study demonstrated that the plasma kisspeptin levels were not totally reduced in lactational or pathological amenorrhea. These results suggest the physiological roles of the circulating kisspeptin are different from the role in the brain.


Subject(s)
Amenorrhea/blood , Kisspeptins/blood , Lactation/blood , Adult , Amenorrhea/etiology , Breast Feeding , Case-Control Studies , Estradiol/blood , Female , Follicle Stimulating Hormone/blood , Humans , Lactation/physiology , Luteinizing Hormone/blood , Postpartum Period/blood , Progesterone/blood , Prolactin/blood
7.
Anticancer Res ; 35(6): 3217-21, 2015 Jun.
Article in English | MEDLINE | ID: mdl-26026081

ABSTRACT

BACKGROUND/AIM: Tumor progression is one of the most serious issues to overcome cancer disease. As a model of inflammation-induced tumor progression, we used the regressive murine fibrosarcoma cell clone QR-32 and the progressive malignant clone QRsP-11, that was derived from QR-32. Heat shock protein beta-1 (Hspb1) is a molecular chaperone. Hspb1 plays roles in not only cell protection but also chemo-resistance, tumorigenicity and protection from apoptosis. In a recent study, we showed that Hspb1 was up-regulated in QRsP-11 compared to QR-32. MATERIALS AND METHODS: We compared the expression levels of Hspb1, Hsf1 and Sox2 in QR-32 and QRsP-11 cells by means of western blotting. RESULTS: Hsf1, a transcription factor for Hspb1 was not increased in QRsP-11. Sex determining region Y-box 2 (Sox2) is a transcription factor, reported to interact with Hspb1. Sox2 was up-regulated in QRsP-11 compared to QR-32. CONCLUSION: These results suggest that Sox2-Hspb1 signaling is a possible pathway responsible to tumor progression of QRsP-11.


Subject(s)
DNA-Binding Proteins/biosynthesis , Fibrosarcoma/genetics , Inflammation/genetics , SOXB1 Transcription Factors/biosynthesis , Transcription Factors/biosynthesis , Animals , Carcinogenesis/genetics , Cell Line, Tumor , DNA-Binding Proteins/genetics , Fibrosarcoma/etiology , Fibrosarcoma/pathology , Gene Expression Regulation, Neoplastic , Heat Shock Transcription Factors , Heat-Shock Proteins/biosynthesis , Humans , Inflammation/complications , Inflammation/pathology , Mice , Molecular Chaperones , Neoplasm Proteins/biosynthesis , Proteomics , SOXB1 Transcription Factors/genetics , Signal Transduction , Transcription Factors/genetics
8.
Endocrine ; 45(2): 236-43, 2014 Mar.
Article in English | MEDLINE | ID: mdl-23695895

ABSTRACT

Although IgG4-related disease is characterized by extensive infiltration of IgG4-positive plasma cells and lymphocytes of various organs, the details of this systemic disease are still unclear. We screened serum total IgG levels in the patients with Hashimoto thyroiditis (HT) to illustrate the prevalence of IgG4-related thyroiditis in HT. Twenty-four of 94 patients with HT (25.5%) had elevated serum IgG levels and their serum IgG4 was measured. Five of the 24 cases had more than 135 mg/dL of IgG4, which is the serum criterion of IgG4-related disease. One was a female patient who was initially treated as Graves' disease and rapidly developed a firm goiter and hypothyroidism. The biopsy of her thyroid gland revealed that follicular cells were atrophic with squamous metaplasia, replaced with fibrosis, which was compatible with the fibrous variant of HT. Immunohistochemical examination revealed diffuse infiltration of IgG4-positive plasma cells, and the serum IgG4 level was 179 mg/dL. The levels of IgG and IgG4 were positively correlated with the titers of anti-thyroglobulin antibody or anti-thyroid peroxidase antibody. In conclusion, at least a small portion of patients with HT with high titers of anti-thyroid antibodies may overlap the IgG4-related thyroiditis.


Subject(s)
Hashimoto Disease/blood , Immunoglobulin G/blood , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Child , Female , Hashimoto Disease/pathology , Humans , Male , Middle Aged , Plasma Cells/pathology , Severity of Illness Index , Thyroid Gland/pathology , Young Adult
9.
Am J Physiol Gastrointest Liver Physiol ; 300(4): G568-76, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21193526

ABSTRACT

Inflammatory bowel disease (IBD) represents a group of chronic inflammatory diseases characterized by inflammation and relapsing gastrointestinal disorders. Recent studies have shown that Th17 cells, which are well known as key mediators of chronic inflammation, have a pivotal role in onset and development of IBD in humans and mice, alike. In recent years, it has been reported that IL-27, which is an IL-12-related heterodimeric cytokine consisting of EBI3 and p28 subunits, act directly on naive T cells to suppress the differentiation of Th17 cells. However, effects of exogenous IL-27 on the IBD are not well elucidated. To clarify the suppressive effect of IL-27 treatment on IBD, we applied the flexible linking method to EBI3 and p28 subunits and generated a single-chain human IL-27 (scIL-27). scIL-27 inhibited xenogenic mouse Th17 cell differentiation in vitro, indicating that scIL-27 also acts in mouse immune systems. In a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced mouse acute colitis model, subcutaneous scIL-27 treatment significantly improved the colon length, extent of necrosis, and ulceration and thickened epithelium and several pathological scores in a dose-dependent manner. scIL-27 clearly suppressed several inflammatory cytokines, including IL-17, in inflamed colon, except for anti-inflammatory cytokine IL-10. The mesenteric lymph node cells from scIL-27-treated mice also exhibited a reduced inflammatory response and, furthermore, a lower population of Th17 cells than those of PBS-treated mice. Finally, we showed the therapeutic efficacy of scIL-27 on TNBS-induced colitis even after active colitis was established. These results suggest new possible therapeutic approaches for IBD, including disorders such as Crohn's disease and ulcerative colitis.


Subject(s)
Colitis/drug therapy , Interleukin-17/therapeutic use , Intestinal Mucosa/drug effects , Th17 Cells/drug effects , Analysis of Variance , Animals , Cell Differentiation/drug effects , Cell Differentiation/immunology , Cell Line , Colitis/chemically induced , Colitis/immunology , Colitis/pathology , Colon/drug effects , Colon/immunology , Colon/pathology , Humans , Interleukin-17/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Male , Mice , Th17 Cells/immunology , Th17 Cells/pathology
10.
Med Hypotheses ; 74(1): 132-8, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19674847

ABSTRACT

Endocrine system has been considered to be a linear one, but the 'real world endocrine system' is a complex system, which is difficult to investigate using conventional strategies, such as single nucleotide polymorphism, genome-wide analysis, or gene targeting in animals. Here we propose a new strategy to comprehend the endocrine system as a complex network system. We introduced several novel concepts, such as complex system, network analysis, systems biology and evolutionary medicine, into the comprehension of endocrine system as a whole complex network system. This system is considered to be a scale-free network with key molecules such as acetyl CoA, NAD or ATP as 'hubs'. This system is robust against simple mutations, but various complex diseases may attack hubs. The system is also 'fractals', since there exist similar network systems among cells, proteins, and transcription factors in the lower levels, and there are similar ones among disease and social network in the higher levels. We propose to call this model 'Integrated Network Systems and Evolutionary DEvelopmental ENdocrinology (INS-EDEN)'. This novel framework will facilitate us to develop a new approach for understanding and treatment of various complex diseases related to endocrinology, and identify a unified theory of complex diseases.


Subject(s)
Developmental Biology/methods , Endocrine System , Endocrinology/methods , Adenosine Triphosphate/metabolism , Coenzyme A/chemistry , Evolution, Molecular , Fractals , Gene Targeting , Genome , Humans , Models, Biological , Models, Theoretical , NAD/chemistry , Polymorphism, Single Nucleotide , Systems Biology
11.
Cancer Sci ; 99(4): 671-6, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18377419

ABSTRACT

We have reported that a lack of RUNX3 function is causally associated with gastric carcinogenesis. We have also presented evidence that loss of Runx3 may be related to the genesis of intestinal metaplasia because expression of RUNX3 is reduced in some intestinal metaplasias, and some Runx3(-/-)p53(-/-) gastric epithelial cells differentiate into intestinal type cells in vivo. Recently several reports have indicated that blood cells play important roles in the gastric carcinogenesis. In the present study, we therefore examined whether Runx3(-/-)p53(-/-) gastric epithelial cells differentiate autonomously into intestinal type cells, or whether the presence of other cells is necessary for the differentiation in vitro. When Runx3(-/-)p53(-/-) gastric epithelial cells were cultured with collagen gels, they did not exhibit any morphogenesis and differentiated poorly. When cultured with fetal mouse gastric mesenchymes, the cells formed glandular structures and differentiated into surface mucous cells, but differentiation of intestinal type cells was never observed. When cultured with Matrigel, the cells formed glandular structures, and some cells differentiated into intestinal type cells in vitro. Reverse transcription-polymerase chain reaction analysis showed that the cells expressed stomach-specific genes, and their levels decreased gradually during the culture. The cells expressed some intestine-specific genes weakly at the start of culture, and their levels were increased with time in culture. We therefore conclude that Runx3(-/-)p53(-/-) gastric epithelial cells differentiate into intestinal type cells in combination with Matrigel in the absence of other cell types. Extracellular matrix, not blood cells, may play a role in the genesis of intestinal metaplasia.


Subject(s)
Cell Differentiation , Core Binding Factor Alpha 3 Subunit/physiology , Gastric Mucosa/cytology , Intestinal Mucosa/cytology , Stomach Neoplasms/etiology , Tumor Suppressor Protein p53/physiology , Animals , Cell Differentiation/genetics , Cell Line , Collagen/chemistry , Collagen/metabolism , Collagen/pharmacology , Core Binding Factor Alpha 3 Subunit/analysis , Core Binding Factor Alpha 3 Subunit/genetics , Drug Combinations , Extracellular Matrix/genetics , Extracellular Matrix/ultrastructure , Gastric Mucosa/drug effects , Gastric Mucosa/physiology , Gene Expression , Intestinal Mucosa/physiology , Laminin/chemistry , Laminin/metabolism , Laminin/pharmacology , Mice , Organ Culture Techniques , Proteoglycans/chemistry , Proteoglycans/metabolism , Proteoglycans/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tumor Suppressor Protein p53/analysis , Tumor Suppressor Protein p53/genetics
13.
Masui ; 55(2): 202-5, 2006 Feb.
Article in Japanese | MEDLINE | ID: mdl-16491900

ABSTRACT

A 15-year-old girl with severe cerebral palsy underwent renal transplantation. It was difficult to anastomose blood vessels because her inferior limbs were contracted. The clamp time was 67 minites. After unclamping, blood pressure fell down from 120/60 to 80/50 mmHg, and CVP fell down from 6 to 3 mmHg. First flow of urine from the donor kidney was noticed 9 hours after unclamping. We regarded difficulty of the operation for cerebral palsy and insufficient infusion as the cause of the late first flow of urine. Two weeks later, there was enough urine flow, and renal function became better. Recently, it is thougt optimal to perform renal transplantations of children who have chronic renal insufficiency and end-stage renal disease. However, there are few reports of renal transplantations for children with cerebral palsy, and there is no guideline for them. Therefore, we anesthesiologists, also have to further examine anesthetic management for each case.


Subject(s)
Anesthesia, Inhalation/methods , Cerebral Palsy/complications , Kidney Transplantation , Adolescent , Female , Humans
14.
Med Hypotheses ; 66(5): 960-3, 2006.
Article in English | MEDLINE | ID: mdl-16414203

ABSTRACT

Epidemiological evidence has established a link among hyperlipidemia, visceral obesity, osteoporosis, and cardiovascular diseases (CVD). We here propose the hypothesis that the associations of those disorders are based on interaction of the three organs, i.e. the bone, adipose, and vascular tissues, possibly through multiple interactions among several humoral factors and/or transcription factors. The unified hypothesis of three organs, which we call 'osteo-lipo-vascular interactions', may be explained by the common origin of the cells in each organ. The mesenchymal stem cells are capable of differentiating into osteoblasts, vascular smooth muscle cells, and adipocytes. Alternatively, macrophages may evolve into osteoclasts or infiltrate both the vascular and adipose tissues, thereby leading to chronic inflammation. This unified concept of three organs may provide insights into the development of a new drug for the treatment of osteoporosis, obesity, hyperlipidemia or CVD.


Subject(s)
Adipose Tissue/physiopathology , Blood Vessels/physiopathology , Bone and Bones/physiopathology , Cardiovascular Diseases/physiopathology , Hyperlipidemias/physiopathology , Obesity/physiopathology , Osteoporosis/physiopathology , Animals , Humans , Models, Biological
15.
Pediatr Nephrol ; 19(4): 442-4, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14677053

ABSTRACT

A 14-year-old girl with rapidly progressive glomerulonephritis was transferred to our hospital because of acute renal failure. A diagnosis of Wegener granulomatosis was made according to the symptom triad of a renal biopsy demonstrating crescentic glomerulonephritis, severe sinusitis, and serological findings of raised proteinase 3 anti-neutrophil cytoplasmic antibody level. In spite of combination therapy with methylprednisolone, cyclophosphamide, and plasma exchange, her renal function gradually deteriorated. Thereafter, she suffered a severe headache and generalized seizures. Brain computed tomography (CT) scan revealed bilateral low-density areas in the parieto-occipital lobes. Magnetic resonance imaging (MRI) disclosed a high-intensity area on T2-weighted images and a low-signal intensity area on T1-weighted images in the same lesion. Follow-up brain CT scan 3 weeks and MRI 2 months after the first studies showed complete resolution of the abnormal lesions, which indicated reversible posterior leukoencephalopathy syndrome. In addition to renal failure, hypertension, and cyclophoshamide, the primary disease may have played a role in the development of this uncommon syndrome in our patient.


Subject(s)
Brain Diseases/etiology , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/physiopathology , Adolescent , Brain/diagnostic imaging , Brain/pathology , Female , Glomerulonephritis/etiology , Headache/etiology , Humans , Hypertension/etiology , Magnetic Resonance Imaging , Seizures/etiology , Tomography, X-Ray Computed
16.
Hypertension ; 42(6): 1183-90, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14670979

ABSTRACT

One of the major causes of end-stage renal diseases is hypertensive renal disease, in which enhanced renal prostaglandin (PG) E2 production has been shown. PGE2, a major arachidonic acid metabolite produced in the kidney, acts on 4 receptor subtypes, EP1 through EP4, but the pathophysiological importance of the PGE2/EP subtypes in the development of hypertensive renal injury remains to be elucidated. In this study, we investigated whether an orally active EP1-selective antagonist (EP1A) prevents the progression of renal damage in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human malignant hypertension. Ten-week-old SHRSP, with established hypertension but with minimal renal damage, were given EP1A or vehicle for 5 weeks. After the treatment period, vehicle-treated SHRSP showed prominent proliferative lesions in arterioles, characterized by decreased alpha-smooth muscle actin expression in multilayered vascular smooth muscle cells. Upregulation of transforming growth factor-beta expression and tubulointerstitial fibrosis were also observed in vehicle-treated SHRSP. All these changes were dramatically attenuated in EP1A-treated SHRSP. Moreover, EP1A treatment significantly inhibited both increase in urinary protein excretion and decrease in creatinine clearance but had little effect on systemic blood pressure. These findings indicate that the PGE2/EP1 signaling pathway plays a crucial role in the development of renal injury in SHRSP. This study opens a novel therapeutic potential of selective blockade of EP1 for the treatment of hypertensive renal disease.


Subject(s)
Hypertension/complications , Kidney Diseases/etiology , Kidney/pathology , Receptors, Prostaglandin E/physiology , Animals , Blood Pressure , Cells, Cultured , Cinnamates , Cyclooxygenase 1 , Fibrosis , Glomerular Mesangium/cytology , Glomerular Mesangium/metabolism , Hypertension/enzymology , Hypertension/genetics , Isoenzymes/metabolism , Kidney/drug effects , Kidney/physiopathology , Kidney Diseases/pathology , Kidney Diseases/physiopathology , Membrane Proteins , Prostaglandin-Endoperoxide Synthases/metabolism , Proteinuria/etiology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Receptors, Prostaglandin E/analysis , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E, EP1 Subtype
17.
Clin Exp Nephrol ; 7(1): 33-40, 2003 Mar.
Article in English | MEDLINE | ID: mdl-14586741

ABSTRACT

BACKGROUND: Connective tissue growth factor (CTGF) is a cysteine-rich growth factor induced by transforming growth factor-beta (TGF-beta) and is thought to play a critical role in TGF-beta-stimulated extracellular matrix accumulation. To explore its involvement in early diabetic nephropathy, we investigated the time course of CTGF gene expression and its regulation in streptozotocin (STZ)-induced diabetic rat kidney. METHODS: Northern blot analysis for CTGF, TGF-beta, and fibronectin expression was performed in the glomeruli of STZ-induced diabetic rats from 3 days to 12 weeks after the induction of diabetes, together with histological examination. To investigate the role of prostanoids in this process, aspirin was administered in one group of diabetic rats. Furthermore, CTGF expression was analyzed in rat mesangial cells cultured under high-glucose conditions. RESULTS: Glomerular expression of CTGF and TGF-beta1 mRNA was coordinately upregulated as early as day 3, followed by fibronectin induction and mesangial matrix accumulation. Chronic aspirin treatment in diabetic rats significantly attenuated mesangial expansion, and effectively suppressed CTGF induction, as well as inhibiting the upregulation of TGF-beta1 and fibronectin expression. In cultured mesangial cells, aspirin treatment abolished high glucose-stimulated CTGF upregulation. CONCLUSIONS: These results indicate that CTGF expressed in the glomeruli is upregulated in the early stage of STZ-induced diabetic nephropathy in rats, and could be a critical mediator of the development of diabetic glomerulosclerosis. In addition, the modulatory effects of aspirin during this process suggest a role of the cyclooxygenase pathway in the progression of diabetic nephropathy.


Subject(s)
Aspirin/administration & dosage , Diabetes Mellitus, Experimental/physiopathology , Immediate-Early Proteins/genetics , Intercellular Signaling Peptides and Proteins/genetics , Prostaglandins/genetics , Animals , Blotting, Northern , Cells, Cultured , Connective Tissue Growth Factor , Cyclooxygenase Inhibitors/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/etiology , Fibronectins/genetics , Gene Expression Regulation/drug effects , Glomerular Mesangium/chemistry , Glomerular Mesangium/drug effects , Glucose/pharmacology , Immediate-Early Proteins/physiology , Intercellular Signaling Peptides and Proteins/physiology , Kidney/pathology , Kidney Glomerulus/chemistry , Kinetics , Male , Prostaglandins/physiology , RNA, Messenger/analysis , Rats , Rats, Wistar , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1
18.
J Am Soc Nephrol ; 14(5): 1154-63, 2003 May.
Article in English | MEDLINE | ID: mdl-12707386

ABSTRACT

Dynamic recovery of glomerular structure occurs after severe glomerular damage in anti-Thy-1 glomerulonephritis (Thy-1 GN), but its mechanism remains to be investigated. To identify candidate genes possibly involved in glomerular reconstruction, screening was performed for genes that are specifically expressed by podocytes and are upregulated in glomeruli of Thy-1 GN. Among them, cysteine-rich protein 61 (Cyr61 or CCN1), a soluble angiogenic protein belonging to the CCN family, was identified. By Northern blot analysis, Cyr61 mRNA was markedly upregulated in glomeruli of Thy-1 GN from day 3 through day 7, when mesangial cell migration was most prominent. By in situ hybridization and immunohistochemistry, Cyr61 mRNA and protein were expressed by proximal straight tubules and afferent and efferent arterioles in normal rat kidneys and were intensely upregulated at podocytes in Thy-1 GN. Platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta1 (TGF-beta1), of which the gene expression in the glomeruli of Thy-1 GN was upregulated in similar time course as Cyr61, induced Cyr61 mRNA expression in cultured podocytes. Furthermore, supernatant of Cyr61-overexpressing cells inhibited PDGF-induced mesangial cell migration. In conclusion, it is shown that Cyr61 is strongly upregulated at podocytes in Thy-1 GN possibly by PDGF and TGF-beta. Cyr61 may be involved in glomerular remodeling as a factor secreted from podocytes to inhibit mesangial cell migration.


Subject(s)
Glomerular Mesangium/cytology , Glomerulonephritis/physiopathology , Immediate-Early Proteins/genetics , Intercellular Signaling Peptides and Proteins/genetics , Neovascularization, Physiologic/physiology , Angiogenesis Inducing Agents/pharmacology , Animals , Antibodies, Monoclonal/pharmacology , Becaplermin , Cell Division/physiology , Cell Line, Transformed , Cell Movement/physiology , Cysteine-Rich Protein 61 , Disease Models, Animal , Gene Expression/drug effects , Gene Expression/physiology , Gene Library , Glomerulonephritis/pathology , Mice , Platelet-Derived Growth Factor/pharmacology , Proto-Oncogene Proteins c-sis , Rats , Thy-1 Antigens/immunology , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta1 , Up-Regulation
19.
J Am Soc Nephrol ; 13(7): 1757-65, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12089371

ABSTRACT

Local production of prostaglandins (PGs) in the kidney is increased in clinical and experimental diabetic nephropathy, but the role of PGs in the pathogenesis and progression of diabetic nephropathy has remained unclear. It is here shown that an orally active antagonist selective for the PGE receptor EP1 subtype potently prevents the progression of nephropathy in streptozotocin-induced diabetic rats. The effects are shown by ameliorated renal and glomerular hypertrophy, decreased mesangial expansion, inhibited transcriptional activation of transforming growth factor-beta (TGF-beta) and fibronectin, and complete suppression of proteinuria. In vitro, this agent completely inhibits TGF-beta and fibronectin upregulation in mesangial cells cultured under high-glucose conditions. These data indicate that the PGE2-EP1 system plays a crucial role in the development of diabetic renal injury in rats. It is further shown that both the EP1 antagonist and aspirin, a nonselective PG synthase inhibitor, markedly attenuate mesangial expansion, whereas only the EP1 antagonist inhibits glomerular hypertrophy and proteinuria, which suggests that these changes are caused by different mechanisms. This study reveals a potential usefulness of selective EP1 blockade as a novel therapeutic strategy for diabetic nephropathy and also brings a new insight into our understanding of this disease.


Subject(s)
Cinnamates/pharmacology , Diabetic Nephropathies/prevention & control , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Aspirin/pharmacology , Autocrine Communication , Cells, Cultured , Cyclooxygenase Inhibitors/pharmacology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Experimental/urine , Dinoprostone/metabolism , Disease Progression , Fibronectins/metabolism , Glomerular Mesangium/drug effects , Glomerular Mesangium/pathology , Hypertrophy , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Kidney Glomerulus/drug effects , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Proteinuria/urine , Rats , Rats, Wistar , Receptors, Prostaglandin E, EP1 Subtype , Tissue Distribution , Transforming Growth Factor beta/metabolism , Up-Regulation/drug effects
20.
Am J Physiol Renal Physiol ; 282(5): F933-42, 2002 May.
Article in English | MEDLINE | ID: mdl-11934704

ABSTRACT

Connective tissue growth factor (CTGF) is one of the candidate factors mediating downstream events of transforming growth factor-beta (TGF-beta), but its role in fibrogenic properties of TGF-beta and in tubulointerstitial fibrosis has not yet been clarified. Using unilateral ureteral obstruction (UUO) in rats, we analyzed gene expression of TGF-beta1, CTGF, and fibronectin. We further investigated the effect of blockade of endogenous CTGF on TGF-beta-induced fibronectin expression in cultured rat renal fibroblasts by antisense oligodeoxynucleotide (ODN) treatment. After UUO, CTGF mRNA expression in the obstructed kidney was significantly upregulated subsequent to TGF-beta1, followed by marked induction of fibronectin mRNA. By in situ hybridization, CTGF mRNA was detected mainly in the interstitial fibrotic areas and tubular epithelial cells as well as in parietal glomerular epithelial cells in the obstructed kidney. The interstitial cells expressing CTGF mRNA were also positive for alpha-smooth muscle actin. CTGF antisense ODN transfected into cultured renal fibroblasts significantly attenuated TGF-beta-stimulated upregulation of fibronectin mRNA and protein compared with control ODN transfection, together with inhibited synthesis of type I collagen. With the use of a reporter assay, rat fibronectin promoter activity was increased by 2.5-fold with stimulation by TGF-beta1, and this increase was abolished with antisense CTGF treatment. Thus CTGF plays a crucial role in fibronectin synthesis induced by TGF-beta, suggesting that CTGF blockade could be a possible therapeutic target against tubulointerstitial fibrosis.


Subject(s)
Fibronectins/genetics , Gene Expression , Growth Substances/physiology , Immediate-Early Proteins/physiology , Intercellular Signaling Peptides and Proteins , Nephritis, Interstitial/physiopathology , Actins/analysis , Animals , Cells, Cultured , Connective Tissue Growth Factor , Epithelial Cells/chemistry , Fibroblasts/metabolism , Fibronectins/biosynthesis , Growth Substances/genetics , Immediate-Early Proteins/antagonists & inhibitors , Immediate-Early Proteins/genetics , In Situ Hybridization , Kidney Glomerulus/chemistry , Kidney Tubules/chemistry , Male , Oligodeoxyribonucleotides, Antisense/genetics , Oligodeoxyribonucleotides, Antisense/pharmacology , RNA, Messenger/analysis , RNA, Messenger/biosynthesis , Rats , Rats, Wistar , Transfection , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/pharmacology , Transforming Growth Factor beta1 , Ureteral Obstruction/physiopathology
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