[Rapidly progressive glomerulonephritis].
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Antibodies, Antineutrophil Cytoplasmic↗
Biomedical subjects
Akio Koyama
Publications and source records attributed to Akio Koyama.
Pseudoreticulocytosis in a patient with hemoglobin Köln due to autofluorescent erythrocytes enumerated as reticulocytes by the Cell-Dyn 4000.
Pseudoreticulocytosis in a 25-year-old female patient with hemoglobin Köln is reported. The abnormal hemoglobin, hemoglobin Köln (beta chain, Val98-->Met), had previously been confirmed in the patient at the age of 21 years, as well as in her mother, by polymerase chain reaction-based direct sequence analysis of the beta globin gene. The patient underwent splenectomy at the age of 22 years. On her admission to our hospital for treatment of an immunoglobulin A nephropathy, an analysis by an automated hematology analyzer, the Abbott Cell-Dyn 4000 (CD4000), reported a marked reticulocytosis. Staining by the Brecher method with new methylene blue indicated a moderate reticulocytosis (5.7%) of a lesser extent than that indicated by the CD4000 (51.1%). The frequencies of red blood cells (RBC) with Pappenheimer bodies (13.8%), Heinz bodies (32.7%), and Howell-Jolly bodies (0.3%) were increased. The CD4000 detects RBC with RNA fluorescently stained with CD4K530 as reticulocytes. Autofluorescence of RBC with hemoglobin Köln, as we demonstrated by flow cytometry and fluorescent microscopy, was considered to have caused the pseudoreticulocytosis on the fully automated reticulocyte enumeration by the CD4000.
Adult↗
[Epidemiology of nephrotic syndrome].
Causes of nephrotic syndrome are varied with age, the times, geographical location and race. In children, minimal change nephrotic syndrome (MCNS) is common; however, membranous nephropathy (MN) is most frequent in adult. Incidence of membranoproliferative glomerulonephritis (MPGN) is decreased in advanced nations, although it remains a common in developing countries. In advanced nations, incidence of focal and segmental glomerular sclerosis (FGS) is increased, particularly in black populations. In Japan, MCNS was most frequent (37.7%), and then, MN was 23.3%, FGS was 7.2% and MPGN was 8.3% by a former research (in 1985). The recent research (in 1994) showed that MCNS was 41.5%, and next MN was 24.7%. FGS was increased to 11.8% and MPGN was decreased to 4.9%.
Age Factors↗
[Mitochondrial dysfunction and focal segmental glomerular sclerosis].
Focal segmental glomerular sclerosis (FSGS) is known as one of major renal complication of mitochondrial cytopathies. Glomerular epithelial cells are primary pathogenic sites in FSGS lesions. Glomerular epithelial cells are regarded as terminally differentiated cells and do not proliferate. This characteristic is the same for neuron cells and muscular cells, which are major sites of mitochondrial DNA mutations accumulation. Accumulation of mitochondrial DNA mutations might induce mitochondrial dysfunction and lead to FSGS lesion in glomeruli or these accumulations are only consequences of pathogenic stimuli to glomerular epithelial cells during the disease course of several glomerulopathies. Further investigations are needed to clarify pathogenic role of mitochondria and mitochondrial DNA mutations.
DNA, Mitochondrial↗
Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels.
Nrf2 is a basic leucine zipper transcriptional activator that is essential for the coordinate transcriptional induction of various antioxidant drug-metabolizing enzymes. Numerous studies have firmly established Nrf2's importance in protection from oxidative stress and certain chemical insults. Given the protective function of Nrf2, surprisingly few studies have focused on the relationship between Nrf2 and apoptosis. Therefore, we analysed how Nrf2 influences Fas signaling using Nrf2-deficient T cells. At a concentration of 1 microg/ml, the anti-Fas antibody induced 60% of cell death in Nrf2-deficient cultured thymocytes while, using the same treatment, only 40% of Nrf2 wild-type thymocytes died (P<0.05). Nrf2 deficiency enhances the sensitivity of Fas-mediated apoptosis in T cells. Next we examined the effect of Nrf2 deficiency during hepatocellular apoptosis in vivo. In comparison to wild-type mice, Nrf2-deficient mice displayed more severe hepatitis after induction with the anti-Fas antibody or tumor necrosis factor (TNF)-alpha. The enhanced sensitivity to anti-Fas or TNF-alpha stimulation was restored by preadministration of glutathione ethyl monoester, a compound capable of passing the cell membrane and upregulating the intracellular levels of glutathione. The results indicated that Nrf2 activity regulates the sensitivity of death signals by means of intracellular glutathione levels.
Animals↗
EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice.
Mice that lack the Nrf2 (NF-E2-related factor 2) transcription factor develop a lupus-like autoimmune nephritis. The tissue-reducing activity of Nrf2-deficient mice was evaluated using a combination of real-time EPR imaging and spin probe kinetic analysis. Substantial delay in the spin probe 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (Carbamoyl-PROXYL) disappearance in the liver and kidneys of Nrf2-deficient mice was observed by EPR imaging. The half-life of the spin probe in the upper abdominal area was prolonged in both the Nrf2-deficient mice and in aged mice. The combination of Nrf2 deficiency and aging in female mice resulted in the most prolonged half-life of disappearance, which was four times longer than that of juvenile female mice with a wild-type genotype. These results indicate that the low reducing activity in these organs is brought about by both Nrf2 deficiency and the aging process, and it may play a key role in the onset of autoimmune nephritis. This combination of the EPR imaging and half-life analysis appears to be a very powerful tool in the real-time analysis of reducing activity.
Animals↗
Dosing time-dependent variation in the hypocalcemic effect of calcitonin in rat.
Dosing time-dependent variation in the hypocalcemic effect of salmon calcitonin was examined in rats under a 12-h light-dark cycle. In both a single-dosing study with normal rats and a repeated-dosing study with hypercalcemic rats (induced by chronic vitamin-D dosing), we consistently observed that the hypocalcemic effect of calcitonin was greater when the drug was given at 14 h after lights on than that at 2 h after lights on. The reduction in urinary deoxypyridinoline excretion, a marker of bone resorption, was also greater when calcitonin was given at 14 h after lights on. Urinary excretion of Ca was not affected by the drug. Pharmacokinetic profiles of calcitonin after a single dosing did not differ between the two trials. These results indicate that the hypocalcemic effect of calcitonin is greater after dosing in the early dark phase (14 h after lights on) than after dosing in the early light phase (2 h after lights on). A time-dependent variation in the sensitivity to the drug of osteoclasts, but not renal tissues, may be involved in the mechanism of this event.
Amino Acids↗
Localization of intercellular adherens junction protein p120 catenin during podocyte differentiation.
To reveal the role of cadherin complex in podocyte differentiation, the present study describes the localization of the cadherin complex, including p120 catenin (p120ctn), in the developing and in the aminonucleoside nephrosis (PAN nephrosis) rat kidney, by immunofluorescence microscopy and immunogold electron microscopy. p120ctn and beta-catenin were co-localized at the apical part of lateral cell membranes in presumptive podocytes of the S-shaped body, and their localization shifted to the basal margin of lateral cell membranes in the capillary loop stage. There was no expression of the cadherin complex at the slit diaphragm, the intercellular junction of mature podocytes. After the regression of the podocyte junctional structure in PAN nephrosis, the cadherin complex was not re-expressed. The dynamic changes in the localization of the cadherin complex suggest that the it plays an important role during podocyte differentiation, including the rearrangement of the intercellular junction and the formation of the slit diaphragm.
Adherens Junctions↗
Oxidative stress during leukocyte absorption apheresis.
Leukocyte absorption apheresis absorbs leukocytes to the apheresis columns involving leukocyte activation. This process is regarded as bioincompatible and avoided in hemodialysis or other extracorporeal circulation processes. Thus, leukocyte apheresis has a potential risk to exacerbate in vivo oxidative stress. We evaluated the changes in plasma oxidative stress during leukocyte apheresis. Patients diagnosed as ulcerative colitis (UC) and treated with leukocyte apheresis were studied. Adacolumn (celluloseacetate beads) or Cellsorba EX (polyethylenephtarate fiber) was used for the leukocyte absorption device. Oxidative stress was measured by thiobarbituric acid reactive substances (TBARS) and hydroxyl radical ((*)OH) scavenging activity. Plasma samples were collected from the pre- and post-column sampling port at the start, and from the pre-column sampling port at the end of the treatment. The (*)OH signal intensities (OHRI) significantly increased during a column passage, indicating a loss of plasma (*)OH scavenging activity. However, OHRI was reduced at the end, suggesting a recovery of radical scavenging activity during leukocyte apheresis. Significant decreases of OHRI and TBARS were only observed in the early phase of the therapeutic course. No differences of OHRI and TBARS levels were observed between the two columns. These results indicate that though the plasma antioxidant activity was diminished by a column passage, plasma antioxidant activity recovers during the procedure. This efficient antioxidative effect is limited to the early phase of the therapeutic course.
Biocompatible Materials↗
Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study.
BACKGROUND: Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection. METHODS: We examined the effect of the angiotensin (AT)1 receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] > or = 140 mmHg or diastolic blood pressure [DBP] > or = 90 mmHg) and CKD (male, body weight [BW] > or = 60 kg: 1.5 < or = SCr < 3.0 mg/dl; female or male BW < 60 kg: 1.3 < or = SCr < 3.0 mg/dl), manifesting proteinuria of 0.5 g or more/day. Losartan was administered once daily at doses of 25 to 100 mg/day, and amlodipine was given once daily at 2.5 to 5 mg/day. No antihypertensive combination therapy was allowed during the first 3-month period. RESULTS: A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group ( n = 43), but there was no change in the amlodipine group ( n = 43). Analysis of stratified subgroups with proteinuria of 2 g or more/day and less than 2 g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2 g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period. CONCLUSIONS: Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action.
Adult↗
Transgenic overexpression of GATA-3 in T lymphocytes improves autoimmune glomerulonephritis in mice with a BXSB/MpJ-Yaa genetic background.
A T helper 1 (Th1)/Th2 imbalance is thought to contribute to the pathogenesis of autoimmune diseases. The differentiation of T cells into Th1 or Th2 subtypes is under the regulation of several transcription factors. Among these, transcription factor GATA-3 is thought to play an indispensable role in the development of T cells and the differentiation of Th2 cells. To examine how a Th1/Th2 imbalance affects the development of autoimmune disease, GATA-3 was overexpressed in the T lymphocytes of C57BL/6 x BXSB/MpJ-Yaa F(1) (Yaa) mice. Yaa mice developed autoimmune nephritis similarly to BXSB/MpJ-Yaa mice, which are commonly used as a model for Th1-dominant murine lupus. GATA-3 overexpression in T cells improved the 50% mortality incidence time for GATA-3-transgenic Yaa mice (41.6 wk), compared with Yaa mice (30.9 wk), and reduced proteinuria, serum creatinine levels, and the severity of glomerulonephritis in GATA-3-transgenic Yaa mice. GATA-3 overexpression in Yaa mice led to simultaneously elevated Th2 Ig (IgG1) and decreased Th1 Ig (IgG2a and IgG3) production and serum IFN-gamma levels. Although IL-4 production remained unchanged, intracellular cytokine analyses demonstrated that IL-5 was induced and IFN-gamma was suppressed in stimulated T cells from the GATA-3-transgenic Yaa mice. These results indicated that abundant GATA-3 was unable to stimulate complete differentiation of Th2 cells but did counteract the dominance of Th1 cells and alleviated the disease severity in Yaa mice. These data suggest that transcriptional regulation therapy may have potential as an effective strategy for treating autoimmune glomerulonephritis.
Animals↗
Electron paramagnetic resonance imaging of nitric oxide organ distribution in lipopolysuccaride treated mice.
The recent development of electron paramagnetic resonance (EPR) permits its application for in vivo studies of nitric oxide (NO). In this study, we tried to obtain 3D EPR images of endogenous NO in the abdominal organs of lipopolysuccaride (LPS) treated mice. Male ICR mice, each weighing about 30 g, received 10 mg/kg of LPS intraperitoneally. Six hours later, a spin trapping reagent comprised of iron and an N-dithiocarboxy sarcosine complex (Fe(DTCS)2, Fe 200 mM, DTCS/Fe = 3) were injected subcutaneously. Two hours after this treatment, the mice were fixed in a plastic holder and set in the EPR system, equipped with a loop-gap resonator and a 1 GHz microwave. NO was detected as an NO-Fe(DTCS)2 complex, which had a characteristic 3-line EPR spectrum. NO-Fe(DTCS)2 complexes in organ homogenates were also measured using a conventional X-band EPR system. NO-Fe(DTCS)2 spectra were obtained in the upper abdominal area of LPS treated mice at 8 h after the LPS injection. 3D EPR tiled and stereoscopic images of the NO distribution in the hepatic and renal areas were obtained at the same time. The NO-Fe(DTCS)2 distribution in abdominal organs was confirmed in each organ homogenate using conventional X-band EPR. This is the first known EPR image of NO in live mice kidneys.
Animals↗
Association of ecNOS gene polymorphisms with end stage renal diseases.
Nitric oxide (NO) is a very potent regulator of intrarenal hemodynamics and is thought to be an important factor in the deterioration of renal function. Several polymorphisms of the endothelial NO synthase (eNOS) gene have been reported. For instance, tandem 27-bp repeats in intron 4 of the eNOS gene are polymorphic, i.e. eNOS4a allele has 4 and eNOS4b has 5 tandem repeats, and the association between eNOS4a and myocardial infarction has been reported. In addition, a missense Glu298Asp mutation in exon 7 of the eNOS gene is reported to be a risk factor for hypertension or myocardial infarction. In this study, we investigated the frequencies of these 2 polymorphisms of eNOS gene in patients with end-stage renal diseases (ESRD), and compared them with those of healthy subjects. Genomic DNA was obtained from regularly hemodialyzed patients and healthy volunteers. The allele frequencies of eNOS4a and eNOS4b in intron 4 were analyzed by PCR and the missense Glu298Asp mutation in exon 7 were determined by PCR FMLP analysis. The allele frequency of eNOS4a (eNOS4a/b and eNOS4a/a) in non-diabetic group is significantly higher than that in healthy controls (27.3% vs. 19.0%, p = 0.01) though there is no significant difference between diabetic group and healthy controls. On the other hand, the frequencies of missense Glu298Asp mutation in both non-diabetic and diabetic groups are significantly higher than that in healthy controls (22.5% in non-diabetic, 20.8% in diabetic and 7.4% in control group, p = 0.002: non-diabetic vs. control, p = 0.01: diabetic vs. control). This study clarified that the polymorphisms in intron 4 and exon 7 of eNOS gene are the genetic risk factors for ESRD. The polymorphisms in intron may change the transcriptional activity and those in exon may alter the 3 dimensional structure of the enzyme, and may affect the progression of renal diseases via decreased NO synthesis. Further study is required to clarify the detailed mechanisms.
Adult↗
Importance of renal mitochondria in the reduction of TEMPOL, a nitroxide radical.
Spin probing methods using an electron spin resonance (ESR) spectrometer are used extensively and bring us a lot of information about in vivo redox mechanisms. However, the in vivo reducing mechanisms of exogenous nitroxide radicals, which serve as typical spin probing reagents are not clear. To clarify this, we examined the sequential kinetics of a spin probe, 4-hydroxy 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPOL) in the in vivo organs, tissue homogenates and subcellular fractions of kidney and liver using an in vivo and X-band ESR spectrometers. As a parameter of reducing activity, we calculated the half-life of TEMPOL from the decay curve of ESR signal intensity. The half-life of TEMPOL in the whole organs and homogenates of the kidney was significantly shorter than that of the liver, this indicates that the kidney has more reducing activity against TEMPOL as compared to the liver. Subcellular fractional studies revealed that this reducing activity of the kidney mainly exists in the mitochondria. Contrarily, in addition to reduction in the mitochondria, TEMPOL in the liver was reduced by the microsome and cytosol.
Animals↗
In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).
We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARbeta-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and the metabolites could regulate the expression of CARbeta target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARbeta activation.
Adjuvants, Immunologic↗
Identification by an EPR technique of decreased mitochondrial reducing activity in puromycin aminonucleoside-induced nephrosis.
The temporal changes in the electron paramagnetic resonance (EPR) signal intensities of a nitroxide radical, 4-hydroxy 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL), in the kidney in rat puromycin aminonucleoside (PAN) nephrosis were investigated in vivo and in vitro. The rats of the PAN nephrosis group received intraperitoneal injections of PAN at 75 mg/kg body weight while those of control group received saline. The in vivo renal half-lives of TEMPOL were calculated from the decay curve of EPR signal intensities after the intravenous injection of the TEMPOL solution. The mitochondrial half-lives were obtained from the decay curve of the EPR signals after mixing the mitochondrial fraction of the kidney and TEMPOL solution. The in vivo half-lives of TEMPOL of the kidney from 7 to 14 d after PAN administration were significantly longer than those of the controls. The mitochondrial half-lives of TEMPOL on the 9th day after the PAN administration prolonged remarkably compared to the controls (378 +/- 69 vs. 676 +/- 183 s, p <.01). These findings indicate that the in vivo and mitochondrial reducing activity in PAN treated rats decreased markedly, because the half-life of TEMPOL in the kidney reflects the renal reducing activity.
Animals↗
[History of nephrology in the last 100 years: Acute rapidly progressive glomerulonephritis].
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Acute Disease↗
[Clinical guideline review: Guidelines for life style and diet in kidney disease].
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Diet Therapy↗