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15-Deoxyspergualin (DSG) inhibited growth of mouse EL-4 lymphoma cells with an IC50 0.02 microg/ml. Even though the cells were treated with DSG for only 4 hours and then washed, the antiproliferative effect lasted long with an IC50 0.4 microg/ml. DSG has spermidine and guanidine moieties in its structure. One decomposed element containing guanidine moiety inhibited the growth at higher doses than DSG, but the effect did not last long unlike DSG. While another element containing spermidine moiety did not affect the growth, it diminished the long-lasting antiproliferative effect of DSG by pretreatment of the cells. Pretreatment with polyamines such as putrescine, spermidine, and spermine also diminished the effect of DSG. Furthermore, N-alkylation of spermidine moiety in DSG abolished the antiproliferative effect. These results suggested that DSG binds to the cells through its spermidine moiety and exerts its long-lasting antiproliferative effect.

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Renal lesions of rats induced by antibodies to cultured rat glomerular epithelial cells (GEC) and mesangial cells (GMC) were studied. Antibodies to cultured rat GEC and GMC were produced by immunization of rabbits with GEC and GMC respectively. The rats injected with anti-GEC antibody showed a small amount of urinary protein, glomerular deposition of rabbit IgG and subepithelial dense deposits observed by electron microscopy. Proteinuria was suppressed in the rats in which complement was depleted with cobra venom factor. Western blot analysis demonstrated a band of 200 KD in GEC lysates reacted with anti-GEC antibody. The rats injected with anti-GMC antibody showed little urinary protein, glomerular deposition of rabbit IgG and mesangial dense deposits. Western blot analysis demonstrated two bands of 43 and 14 KD in GMC lysates reacted with anti-GMC antibody. These data showed that the injection of anti-GEC antibody or anti-GMC antibody induced similar lesions to passive Heymann nephritis and anti Thy 1.1 nephritis. This study suggested that antigenicity of structural glomerular cells is important as the antigens of glomerulonephritis.

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Fibrin formation within the glomeruli occurs in various forms of human and experimental glomerulonephritis and it may play an important role in progressive glomerular injury. Transforming growth factor-beta (TGF-beta) has been shown to participate in the glomerular accumulation of extracellular matrix in glomerulonephritis. We investigated whether thrombin, an important coagulation factor, could modulate the production of TGF-beta by cultured human mesangial cells (HMC). TGF-beta levels in the culture supernatants were measured by ELISA using a specific antibody. The TGF-beta concentration was significantly increased by incubation of HMC with thrombin in a time-dependent manner. The stimulating effect of thrombin on TGF-beta was inhibited by addition of hirudin (a natural thrombin inhibitor) and argatroban (a synthetic thrombin inhibitor). In addition DFP-inactivated thrombin, which has no enzymatic activity, did not stimulate TGF-beta production. A protein kinase C inhibitor (H7) and a tyrosine kinase inhibitor (herbimycin A) also inhibited thrombin induced TGF-beta production. These findings suggested that thrombin may modulate the synthesis of TGF-beta via protein kinase C- and tyrosine kinase-dependent mechanisms in cultured HMC. Thus thrombin may participate in the accumulation of extracellular matrix in glomeruli through the augmentation of TGF-beta production.

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We report a case of Sjögren's syndrome whose clinical course had been indolent until the patient presented with Sweet's syndrome (acute febrile neutrophilic dermatosis). This patient showed renal failure and renal tubular acidosis. Sweet's syndrome resolved within 3 weeks without corticosteroid therapy. Renal biopsy findings were consistent with interstitial nephritis. His renal manifestations responded to corticosteroid therapy and the renal function remained stable during 6 years follow-up without recurrence of Sweet's syndrome. Although close association of both syndromes is already known, in our case Sjögren's syndrome may have been exacerbated by occurrence of Sweet's syndrome.

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Fibrin formation within the glomeruli has been observed in various forms of human and experimental glomerulonephritis and it may play an important role in progressive glomerular injury. Furthermore it has been hypothesized that glomerular fibrin deposition may occur through activation of either the intrinsic or extrinsic coagulation pathway. It has been demonstrated that a procoagulant activity (PCA) which is compatible with tissue factor is present in the glomeruli and becomes increased in human proliferative glomerulonephritis and in animal models of nephritis. Tissue factor pathway inhibitor (TFPI) regulates the extrinsic pathway of blood coagulation through its ability to inhibit tissue factor activity. TFPI is present in plasma and in platelets, and it is now thought to be produced mainly by endothelial cells. We examined whether human mesangial cells (HMC) could produce TFPI and attempted to clarify regulatory factors which affect TFPI production. Cultured HMC were used and TFPI in the cell supernatants was measured by ELISA using a specific antibody. Cultured HMC showed the production of TFPI. Immunoblot analysis revealed 40 kD protein of TFPI. The concentration of TFPI was significantly increased following the incubation with thrombin and heparin, including low molecular weight heparin, in a dose- and time-dependent manner. However, fetal calf serum, phorbol myristate acetate, lipopolysaccharide, IL-1 beta and tissue factor did not stimulate TFPI synthesis. Our data show that cultured HMC have the ability to produce TFPI which inhibits fibrin formation. It is possible that thrombin-induced enhancement of TFPI synthesis may be caused by the autoregulatory system of blood coagulation and that with heparin it may represent another anticoagulatory effect of heparin.

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We studied whether urinary findings are affected by stimulation of tonsils in patients with IgA nephropathy. In 62 patients with IgA nephropathy and 20 patients with other renal diseases tonsils were stimulated by an ultra short wave for 10 min. Changes in amount of urinary protein, urinary sediment, blood leucocyte count, concentrations of serum IgA and serum secretory IgA were evaluated after tonsil stimulation. Forty of 62 patients with IgA nephropathy (65%) showed deterioration of urinary findings after the stimulation compared with 6 of 20 patients with other renal diseases (30%). The deterioration was significantly more frequent in IgA nephropathy than in other renal diseases (p <0.005). Previous episodes of gross hematuria following upper respiratory tract infections had occurred in 17 of 40 patients who showed deterioration of urinary findings after tonsil stimulation (43%) as against in 4 of 22 without deterioration (18%). The level of serum secretory IgA was higher in patients who showed deterioration of urinary findings after tonsil stimulation than in those who did not show it. Though tonsil stimulation increased blood leucocyte count it did not affect the concentrations of serum IgA or secretory IgA. It is concluded that tonsil stimulation often deteriorates urinary findings in patients with IgA nephropathy; therefore chronic tonsillitis may play a part in the pathogenesis of IgA nephropathy.

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The prevalence of hepatitis C virus (HCV) infection was determined in 146 adult patients with various types of glomerulonephritis and renal diseases monitored between 1990 and 1993. Serum HCV antibody (HCV Ab) was evaluated, and positive cases were tested for HCV RNA by polymerase chain reaction. HCV infection was present in 1 (1.7%) of 58 cases of immunoglobulin A nephropathy, 0 (0%) of 14 cases of lupus nephritis, 0 (0%) of 12 cases of minimal change nephrosis, and 0 (0%) of 28 cases of other renal diseases, which is similar to the 2% prevalence observed in healthy blood donors in Japan. In contrast, HCV Ab was observed in 2 (8.3%) of 24 cases of membranous nephropathy and 6 (60%) of 10 cases of membranoproliferative glomerulonephritis (MPGN) Type I. The prevalence of HCV infection in MPGN patients was significantly higher than the frequency of HCV infection observed in the other patients with renal diseases (P < 0.001). HCV RNA was present in all cases in which HCV Ab was present. The six patients with HCV-MPGN were similar to the four patients with idiopathic MPGN with respect to age, presence of nephrotic syndrome, and renal dysfunction, but had a higher incidence of liver dysfunction, cryoglobulinemia, rheumatoid factor, and hypocomplementemia (low C3). HCV infection is present in a large percentage of patients with MPGN in Japan and clinically may differ slightly from other cases of MPGN.

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New triene-ansamycins designated thiazinotrienomycins A, B, C, D and E were isolated from culture broth of Streptomyces sp. MJ672-m3 for their activities against cervical cancer cell lines. The structures and some biological and biochemical properties of the antibiotics were determined.

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A new structural class of the antibiotic, azicemicins A (1) and B (2) were isolated from the culture broth of the strain MJ126-NF4, which was closely related to Amycolatopsis sulphurea. They were purified by adsorption on Diaion HP-20, silica gel column chromatography and preparative TLC. The molecular formulas of 1 and 2 were determined to be C23H25O9N and C22H23O9N by HRFAB-MS, respectively. Azicemicins A and B have moderate growth inhibiting activity against Gram-positive bacteria and mycobacteria.

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BACKGROUND: Glomerular epithelial cells (GECs) play an important role in maintaining normal glomerular permselectivity in vivo. Recent in-vitro studies have suggested that GECs are able to secrete substances which may modulate glomerular injury. Interleukin 6 (IL-6) has been shown to be a potent mediator of glomerular injury. It is also known that IL-6 could be produced by various cells. METHODS: IL-6 production by rat GECs in culture was examined in this study. IL-6 bioactivity in conditioned medium collected from cultured GECs (GEC-CM) was measured using IL-6 dependent murine hybridoma cell line, namely B9 cells. IL-6 gene expression by GECs was analysed by reverse transcriptase polymerase chain reaction (RT-PCR). Effects of recombinant IL-6 on the proliferation of GECs and type IV collagen secretion by GECs were evaluated to examine the possible role of GECs derived IL-6. RESULTS: GEC-CM stimulated B9 cells growth in a dose dependent fashion. The mitogenic activity was inhibitable by anti-murine IL-6 antibody. De-novo synthesis of IL-6 was suggested by the demonstration of IL-6 mRNA by GECs using the RT-PCR. Secretion of IL-6 by GECs was increased by transforming growth factor beta but not by IL-1 beta. Recombinant murine IL-6 stimulated GECs growth and their type IV collagen secretion. CONCLUSIONS: These results indicate that rat GECs could produce IL-6 which may modulate glomerular inflammation and that IL-6 may function as an autocrine factor for GECs.

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A 42-year-old man with hepatitis C virus infection, cryoglobulinemia, hypocomplementemia, and nephrotic syndrome is reported. The kidney biopsy showed membranoproliferative glomerulonephritis. The patient was treated with interferon-alpha for 2 months. After the treatment, serum hepatitis C virus RNA became negative and nephrotic syndrome remitted. Repeat biopsy of the kidney revealed an improvement in renal histology. This case confirms an association between hepatitis C virus infection and membranoproliferative glomerulonephritis and the usefulness of interferon-alpha for treatment.

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Fibrin/Fibrinogen degradation products (FDP) and cross-linked FDP (XLFDP) have been found in the urine of many patients with renal disease. FDP result from fibrinogenolysis and fibrinolysis. It is useful to detect the urinary XLFDP which results from fibrinolysis in order to diagnose intraglomerular coagulation. I investigated urinary FDP and XLFDP in patients with various renal diseases. Urinary FDP and XLFDP were detected by latex aggregation test in the urine of 96 patients. Urinary XLFDP was measured by enzyme-linked immunosorbent assay (ELISA) using monoclonal antibody in the urine of 140 patients. The positive rates of urinary XLFDP were higher in chronic renal failure, membranous nephropathy and membranous-proliferative glomerulonephritis than in other renal diseases. High levels of urinary XLFDP were found in membranous nephropathy, membranous proliferative glomerulonephritis and non-IgA nephropathy. There was an obvious relationship between urinary XLFDP and the degree of proteinuria, hematuria, serum creatinine and intraglomerular fibrin deposits. The high levels of urinary XLFDP were detected in the case of severe proteinuria, normal and mild hematuria, normal and slightly increased serum creatinine and mild intraglomerular fibrin deposits.

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We report here an old male patient with anti-nuclear antibody (ANA) negative systemic lupus erythematosus (SLE) with active renal disease and penile ulcer. He revealed nephrotic syndrome, malar rash and oral ulcer. SLE was discussed, however both ANA and anti-DNA antibody were persistently negative. A penile ulcer was also observed. He died of acute respiratory distress. Autopsy findings including onion skin lesion in the spleen and haematoxylin body in the kidney resulted in the final diagnosis of SLE. To our knowledge, association of penile ulcer with SLE has not yet been reported. Therefore, the present case is thought to be extremely unusual.

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It is well known that fibrin deposition in Bowman's space in association with crescent formation may play an important role in progressive glomerular injury in crescentic glomerulonephritis. Recent reports describe the presence of a procoagulant activity (PCA) in the glomeruli and its increased expression in human and experimental nephritis. The cells that synthesize PCA have not yet been identified. We attempted to determine if glomerular epithelial cells (GEC), one of the prominent cell populations in the crescent, can produce PCA. The PCA of cultured rat GEC was measured by clotting and amidolytic assays. The cultured GEC yielded PCA with the characteristics of a tissue factor, and this PCA was stimulated by interleukin 1, tumour necrosis factor-alpha, and lipopolysaccharide. We concluded that GEC produce tissue-factor-like PCA and thereby may contribute to fibrin deposition, which, along with macrophage or monocyte infiltration, leads to crescent formation in crescentic glomerulonephritis.

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A few cases of nephrotic syndrome with the glomerular deposition of an amyloid-like material which did not stain with Congo red have been documented. But extrarenal deposits have not been previously reported in this disease. We describe here a case of nephrotic syndrome associated with the deposition of an amyloid-like material in the liver as well as in the renal glomeruli. The deposits were made up of fibrillar structures which resembled those of amyloid when viewed through the electron microscope but they did not stain with Congo red. This is the first report of amyloidosis-like glomerulopathy with extrarenal deposits.

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Serum secretory IgA was measured to elucidate the significance of secretory IgA in patients with IgA nephropathy. The levels of serum secretory IgA and IgA were, respectively, 6.8 +/- 3.5 micrograms/ml and 231.0 +/- 69.2 mg/dl in the controls and 11.8 +/- 3.2 micrograms/ml and 385.3 +/- 78.7 mg/dl in the patients. The levels of serum secretory IgA and IgA in the patients were significantly higher than those in controls (p less than 0.01). Elevated serum secretory IgA may reflect the excessive state of the IgA-secreting system in IgA nephropathy patients.

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