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Yoshiki Morita

Publications and source records attributed to Yoshiki Morita.

12 recordsLinked to original sources
PubMed2005

A useful new classification of dysmorphic urinary erythrocytes.

BACKGROUND: Among dysmorphic urinary erythrocytes (D cells), G1 cells or doughnut-shaped erythrocytes with one or more blebs are considered to be reliable markers for glomerular diseases. However, although there are many D cells with cytoplasmic color loss and without blebs in the urinary sediment, the significance of these cells is not clear. In this study, we devised a classification system for D cells and examined the relation between these cell types and urinalysis data. METHODS: We classified D cells into three types (D1, D2, and D3 cells): D1 cells showed a ring-like shape and severe loss of cytoplasmic color with protrusions or blebs; D2 cells showed a doughnut-like shape and moderate cytoplasmic color loss with protrusions or blebs; and D3 cells showed a doughnut-like shape and mild cytoplasmic color loss without protrusions or blebs. We calculated the numbers of D cells of each type in 45 patients with glomerular diseases and in 303 general outpatients. This was done by bright-field microscopy modified for the analysis of urinary sediment, and we also examined the significance of these cell types. RESULTS: In the 45 patients with glomerular diseases, the numbers of D1, D2, and D3 cells correlated with urine levels of proteinuria and hematuria and numbers of cellular and fatty casts. Numbers of D1 and D2 cells correlated with urine concentrations of albumin and N-acetyl-beta-D-glucosaminidase, and the proportions of D1 and D2 cells in D cells increased with the activity of glomerular diseases classified by urinalysis data. Only the number of D1 cells correlated with the urine concentration of potassium, which may increase in hemolysis. In the 303 outpatients, the sensitivity of D3 cells and D1 and/or D2 cells (G1 cells) was 73% and 46%, respectively, for the detection of glomerular diseases and the specificity was 93% and 99%, respectively. CONCLUSIONS: These data indicate that the D3 cell is a sensitive marker for glomerular diseases, and that D1 and/or D2 cells are markers for severe glomerular diseases.

Acanthocytes↗
PubMed2005

Geranylgeranylacetone ameliorates ischemic acute renal failure via induction of Hsp70.

BACKGROUND: Heat shock proteins (HSPs) are well known as cytoprotective proteins. Geranylgeranylacetone (GGA), an antiulcer agent, has recently been shown to induce Hsp70. This study was performed to investigate the renoprotective properties of GGA. METHODS: The effect of GGA on the induction of the major HSPs (Hsp90, Hsp70, Hsc70, Hsp60, and Hsp32) was studied in the rat kidney or rat primary cultures of tubular epithelial cells (R-TECs) by Western blot. Localization of Hsp70 was determined by immunohistochemistry. The renoprotective effects of GGA were studied using a rat model of ischemia/reperfusion (I/R) injury. GGA (400 mg/kg), GGA with quercetin pretreatment (100 mg/kg), or a vehicle was given to rats 24 hours and again 1 hour prior to the induction of I/R injury. Rats were sacrificed at 24 hours after reperfusion. Histologic analyses and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL) assay were performed. Blood urea nitrogen (BUN) and serum creatinine was also measured. The cytoprotective properties of GGA were also studied in vitro by treating R-TECs with GGA (10 mumol/L) or a vehicle, followed by incubation in culture medium with oxidative stress condition (0.5 mmol/L hydrogen peroxide) or ischemic condition (2 nmol/L NaCN and 20 mmol/L 2-deoxyglucose in the absence of medium glucose). RESULTS: Oral administration of GGA induced Hsp70 expression in the kidney (which peaked at 24 hours) but did not induce Hsp90, Hsc70, Hsp60, or Hsp32. The induction of Hsp70 was blocked by quercetin. Immunohistochemistry showed that Hsp70 was localized mainly in the tubular epithelial cells. Preconditioning rats with GGA significantly decreased BUN and serum creatinine levels after I/R injury. Histologic examination revealed that GGA significantly attenuated tubular damage and macrophage infiltration. The number of TUNEL-positive cells also decreased significantly in the GGA group. Quercetin, an inhibitor of Hsp70 induction, eliminated these renoprotective effects of GGA. In in vitro study, GGA-induced Hsp70 in R-TECs, which peaked at 2 to 4 hours. Both oxidative stress and ischemic stimuli induced apoptosis in R-TECs. GGA significantly suppressed the number of apoptotic cells in both conditions. CONCLUSION: The results support the hypothesis that GGA induces Hsp70, protects tubular epithelial cells from apoptosis, and thus ameliorates tubular damage by I/R injury. The present study suggests that GGA would be a useful tool in treating acute renal failure or preventing transplanted kidney damage in the clinical setting.

Acute Kidney Injury↗
PubMed2005

[Clinical efficacy of shortened ACTH therapy --an individualized method for minimization of adverse effects--Part 1. The short-term outcome].

To minimize adverse effects and to get good efficacy of ACTH therapy against West syndrome, we tried a new 2-steps therapeutic protocol consisting of the shortened ACTH therapy and the additional ACTH therapy. In a prospective multi-institutional study, 20 patients with newly diagnosed West syndrome who had failed to respond to high-dose vitamin B6 and zonisamide were treated by this shortened ACTH therapy. Synthetic corticotropin (ACTH-Z 0.025 mg/kg/dose, max 0.25 mg) was administrated intramuscularly seven times on every other day for 14 days. At 1 month after discontinuing corticotropin, spasms and hypsarrhythmia disappeared in 10/20 (50%) and 13/17 (59%) patients respectively. Subsequently, 9 out of the 10 patients with persistent spasms received additional therapy for 1 or 2 weeks with daily intramuscular ACTH-Z, which was tapered off over a few weeks. Including the additional ACTH therapy, the disappearance of spasms and hypsarrhythmia were found in 13 patients (65%) and 13 patients (76%). Adverse effects during the shortened ACTH therapy were fewer than additional ACTH therapy but not statistically significant. Severe adverse effects were not observed in both ACTH therapy. In the 2-steps therapeutic protocol according to the response to ACTH, favorable results were obtained in seizure control, EEG findings and the degree of adverse effects.

Adrenocorticotropic Hormone↗
PubMed2004

In vivo gene transfer of endo-beta-galactosidase C removes alphaGal antigen on erythrocytes and endothelial cells of the organs.

BACKGROUND: The presence of Galalpha1-3Galbeta1-4GlcNAc (alphaGal) in pigs is a formidable barrier for pig-to-primate xenotransplantation. We have reported that administration of recombinant endo-beta-galactosidase C (EndoGalC) removes alphaGal on porcine erythrocytes and kidneys. The present study examined the effects of EndoGalC gene therapy on alphaGal suppression. METHODS: Naked plasmid DNA encoding Igkappa-EndoGalC was given to rats by rapid tail vein injection. The expression of alphaGal in the heart and kidney were studied by lectin staining followed by computer-assisted quantitative analyses. alphaGal expression on erythrocytes was determined by flow cytometric analyses. Enzymatic activity of EndoGalC in the serum was also determined by evaluating the capacity of EndoGalC in removing alphaGal epitopes. Elimination of alphaGal was further studied by injecting antibodies against alphaGal to rats 2 days after the gene transfer. RESULTS: Administration of 1 mg of Igkappa-EndoGalC/pCAGGS plasmid eliminated alphaGal from the vascular endothelium of the heart and kidney on day 1 and day 2. Between days 4 and 7, alphaGal started to reappear, but remained suppressed. No serious adverse effect was observed in rats treated with EndoGalC. Flow cytometric analyses showed that EndoGalC digested 97% of alphaGal on erythrocytes when measured 4 days after the gene transfer. Enzymatic activity of EndoGalC in the serum peaked on day 1, and significant levels were still observed on day 7. When antibodies against alphaGal were given, rats treated with EndoGalC showed no change, while all control rats died within 40 min. CONCLUSIONS: The present study demonstrates the potential of an EndoGalC gene transfer, using a hydrodynamics-based delivery system, in eliminating alphaGal from endothelial cells in vivo. The results also ensured that EndoGalC is not harmful suggesting that the production of pigs overexpressing EndoGalC would be a reasonable alternative to pigs deficient in alpha1,3galactosyltransferase.

Animals↗
PubMed2004

Endotoxin-induced chemokine expression in murine peritoneal mesothelial cells: the role of toll-like receptor 4.

Acute peritonitis, in which peritoneal mesothelial cells are directly exposed to bacterial components, is a major cause of peritoneal dysfunction in continuous ambulatory peritoneal dialysis patients. We have previously shown that Toll-like receptors (TLR) are expressed in kidney cells, and LPS induces TLR4-dependent chemokine production in tubular epithelial cells. The present work was designed to investigate the involvement of TLR, especially TLR4, in the lipid A-mediated chemokine production by murine peritoneal mesothelial cells (MPMC). A primary cell culture of MPMC from C3H/HeN mice (wild-type mice; LPS sensitive) and from C3H/HeJ mice (containing a point mutation of TLR4; LPS hyposensitive) was established. The expression profile of the TLR family and their accessory molecules, CD14 and MD-2, which are requisite for the LPS signaling pathway, was examined by RT-PCR, Northern blot test, and immunohistochemical staining. Synthetic lipid A-mediated chemokine production by MPMC was studied. The involvement of MAP kinase family (ERK, JNK, and p38 mitogen-activated protein kinase) and nuclear factor (NF)-kappaB in these processes was also studied. MPMC constitutively express TLR4, CD14, and MD-2. A prominent induction of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein (MIP)-2 by MPMC was detected after lipid A stimulation and was strictly dependent on TLR4. Furthermore, TLR4-dependent chemokine production followed by leukocyte influx into the peritoneal cavity was also confirmed in vivo after stimulation with LPS. mRNA expression of MCP-1 was abolished by NF-kappaB inhibition, but were not affected by the inhibition of ERK, JNK, or p38. As compared with MCP-1, MIP-2 mRNA expression was inhibited by a high dose of curcumin but not by NF-kappaB decoy oligodeoxynucleotide and individual inhibitions of MAP kinase, suggesting that the additional signaling pathway with NF-kappaB might be involved in mRNA expression of MIP-2. These show that TLR4 is directly involved in the production of MCP-1 and MIP-2 by MPMC in a NF-kappaB-dependent manner, but the process does not require any MAP kinase activation. The results provide a candidate molecular target in prevention of it.

Animals↗
PubMed2003

The nephrotoxicity of Aristolochia manshuriensis in rats is attributable to its aristolochic acids.

BACKGROUND: Although Aristolochia manshuriensis (AM), which was incriminated in the Japanese variety of Chinese herbs nephropathy, has been recently shown to be nephrotoxic in rats, less is known about whether this toxicity is attributable to its aristolochic acids (AA). We compared the renal effect of AM with that of Akebia quinata (AQ), which has similar components to AM but is free of AA; we also compared this effect of AM with that of pure AA, and studied its possible mechanism. METHODS: In study 1, rats were divided into four groups. Each group was orally given either 0.4 g of AM, 4 g of AM, or 4 g of AQ per day, or vehicle, for 5 days. In study 2, rats were given 4 g of AM (which contained 4 mg of AA), or 4 mg of pure AA per day, or vehicle, for 5 days. Renal function, and renal histology were evaluated on day 5 in study 1 and on days 1, 3, 5, and 14 in study 2. In study 2, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) staining were also performed. In study 3, rats were treated in the same way as in study 2, but were all killed on day 5. Concentrations of AA (I + II) were measured in serum and urine in study 2, and in the kidney, lung, heart, liver, and spleen in study 3. RESULTS: In study 1, only the rats that received 4 g/day of AM developed tubular necrosis, azotemia, proteinuria, and glucosuria. In study 2, both AM- and AA-treated rats showed progressive tubular damage, decreased renal function, and increased urinary protein excretion. The degree of these alterations was comparable in the AM and AA groups. Moreover, the concentrations of AA (I + II), in serum, urine, and kidney were also comparable in the AM- and AA-treated rats. High levels of AA were detected in the lung and kidney. Apoptotic tubular cells increased on day 5 and had decreased by day 14 after the withdrawal of AM or AA. Meanwhile, proliferating tubular cells progressively increased from day 3 to day 14. CONCLUSIONS: Our study indicates that the renal toxicity of AM can be attributed to its AA component. Tubular cell apoptosis might be one of the mechanisms involved in this renal injury.

Animals↗
PubMed2003

Non-dipping is a potent predictor of cardiovascular mortality and is associated with autonomic dysfunction in haemodialysis patients.

BACKGROUND: Lack of nocturnal blood pressure (BP) fall (non-dipping) is common among haemodialysis (HD) patients, but much less is known regarding its association with cardiovascular (CV) disease morbidity and mortality. METHODS: Eighty HD patients initially underwent 24 h ambulatory BP monitoring (ABPM), and then they were defined as either 'dippers' (n=24, nocturnal BP fall > or = 10%) or 'non-dippers' (n=56, fall <10%). Coronary angiography was performed in the patients who had signs and/or symptoms of coronary artery disease (CAD). Twenty-four hour ambulatory ECG was recorded in 20 dippers and 20 non-dipper HD patients, and in 20 normal subjects. All patients were followed for up to 5.8 years (33.0+/-19.1 months). The outcome events studied were the hospitalisations due to CV diseases and CV death. RESULTS: Compared with dippers, non-dippers initially had a higher incidence of coronary artery stenosis (P<0.05) along with left ventricular asynergy (both Ps<0.01). The circadian rhythm of autonomic function was impaired in non-dippers. The incidences of CV events and CV deaths were 3.5 and 9 times higher in non-dippers than in dippers. The cumulative CV event-free survival and CV survival rates were lower in non-dippers than in dippers (P=0.02 and P=0.005, respectively). Based on Cox analysis, non-dipping was associated positively with CV events and CV mortality [hazard ratio (HR) 2.46, 95% CI 1.02-5.92, P=0.038 and HR 9.62, 95% CI 1.23-75.42, P=0.031, respectively]. Meanwhile, nocturnal systolic BP fall, diurnal systolic BP and diurnal pulse pressure were negatively associated with CV event/death. The clinic BP was not associated with CV event/death. CONCLUSIONS: The non-dipping phenomenon is closely related to a high incidence of CV diseases, a poor long-term survival and profound autonomic dysfunction. ABPM is useful in predicting long-term CV prognosis in HD patients.

Aged↗
PubMed2003

Anti-monocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria.

It has been postulated that protein filtered through glomeruli activates tubular epithelial cells, which secrete vasoactive and inflammatory substances including chemokines, leading to tubulointerstitial renal injury. The present study was designed to investigate the role of monocyte chemoattractant protein-1 (MCP-1) in this process and to evaluate the effectiveness of a kidney-targeted gene transfer technique using hydrodynamic pressure. Naked plasmid encoding 7ND (an MCP-1 antagonist) or a control plasmid was introduced into the left kidney of rats. Three days after gene transfer (day 0), intraperitoneal administration of bovine serum albumin (10 mg/g body wt per day) was started and continued for 14 or 21 d. RT-PCR showed that 7ND mRNA was expressed only in the gene-transfected kidney. Immunostaining showed that 7ND protein was localized in the interstitial cells. Macrophage infiltration was significantly reduced in the left kidney of rats treated with 7ND on days 14 and 21. In the right kidney, such effects were not observed. 7ND also attenuated tubular damage and decreased the number of apoptotic cells. Computer-assisted analysis revealed that the areas positively stained for alpha-smooth muscle actin (alpha SMA), fibronectin-EDA, type I collagen, and collagen fibrils were significantly reduced in the 7ND-treated kidney on day 21. Furthermore, 7ND gene therapy significantly reduced MCP-1 and TGF-beta 1 mRNA expression. These results demonstrate that MCP-1 plays an important role in the development of tubulointerstitial inflammation, tubular damage, and fibrosis induced by proteinuria. The fact that 7ND gene therapy had little effect on the contralateral kidney indicates that 7ND acted locally. This strategy may have a potential usefulness as a gene therapy against tubulointerstitial renal injury.

Animals↗
PubMed2002

Effects of human soluble thrombomodulin on experimental glomerulonephritis.

BACKGROUND: Coagulation and inflammation are both important processes that contribute to glomerular injury. The present study was performed to evaluate the effects of recombinant human soluble thrombomodulin (RHS-TM) in a lethal model of thrombotic glomerulonephritis and to investigate the possible mechanisms. METHODS: Thrombotic glomerulonephritis was induced in rats by administration of lipopolysaccharide and rabbit anti-rat glomerular basement membrane antibody. One hour later, RHS-TM or heparin was administered, and the histological findings, renal functions, and coagulation parameters were evaluated. To evaluate the contribution of carboxypeptidase R (CPR) to the results obtained in rats treated with RHS-TM, plasma CPR levels were measured. Then, carboxypeptidase inhibitor (CPI), which prevents the function of CPR, was administered. RESULTS: Massive glomerular thrombosis and lung hemorrhage developed within five hours of disease induction, and all rats died within 24 hours. RHS-TM (3 mg/kg) prevented the progression of the disease and all rats survived. Heparin (250 U/kg/h) showed similar anti-thrombotic effect, but induced massive hemorrhage in the lungs or stomach. RHS-TM attenuated leukocyte/neutrophil infiltration in the glomerulus but heparin did not, suggesting that RHS-TM has anti-inflammatory properties. CPR levels in plasma were about threefold higher in rats treated with RHS-TM compared to those in rats treated with heparin. Furthermore, the inhibitory effect of RHS-TM on leukocyte/neutrophil infiltration was significantly diminished by injection of CPI. CONCLUSION: RHS-TM effectively attenuates the injuries of thrombotic glomerulonephritis in rats. The results indicate that RHS-TM, in addition to its anti-thrombotic action, may exert its anti-inflammatory properties by converting proCPR to CPR, which then inactivates anaphylatoxins. RHS-TM is a potential novel therapeutic tool for thrombotic glomerular injury and related disorders.

Anaphylatoxins↗
PubMed2000

Complement activation products in the urine from proteinuric patients.

The presence of plasma proteins in the tubular lumen has variety of adverse effects on the tubular cells. Among various plasma proteins filtered through glomerular barrier, complement has been proven as the possible candidate inducing tubulointerstitial injury. To study the role of intratubular complement activation in proteinuric patients, complement activation products (CAP) at C3 level (iC3b and Bb) and C9 level (membrane attack complex) were measured in both plasma and urine of patients with minimal change nephrotic syndrome (MCNS), focal glomerular sclerosis, IgA nephropathy, membranous nephropathy, and diabetic nephropathy. For evaluation of the effect of metabolic acidosis on the intratubular complement activation, urinary CAP were measured before and after sodium bicarbonate administration in patients with renal insufficiency. The following results were obtained: (1) Patients with focal glomerular sclerosis and diabetic nephropathy showed the highest level of urinary CAP excretion rate (unit/creatinine), while MCNS revealed no increase. (2) Patients with membranous nephropathy showed a unique finding, i.e., isolated increase of membrane attack complex excretion. (3) There was no significant correlation between urine and plasma levels of CAP. (4) Except for MCNS patients, the urinary excretion rate of CAP significantly increased when the level of proteinuria exceeded the nephrotic range, and it was significantly correlated with the serum creatinine level. (5) Urinary CAP excretion rate significantly decreased 2 wk after sodium bicarbonate administration without affecting the level of proteinuria or plasma CAP. These results suggest that the degree of intratubular complement activation correlates with the level of proteinuria, type of glomerular disease, impairment of renal function, and metabolic acidosis.

Adolescent↗