Targeted IgA Fc receptor I (FcαRI) therapy in the early intervention and treatment of pristane-induced lupus nephritis in mice.

The Fc receptor I for IgA (FcαRI) down-regulates humoral immune responses and modulates the risk of autoimmunity. This study aimed to investigate whether FcαRI targeting can affect progression of pristine-induced lupus nephritis. In the first experiment (early intervention), four groups of animals were evaluated: untreated FcαRI/FcRγ transgenic (Tg) mice and Tg mice administered control antibody (Ctr Fab), saline and anti-FcαRI Fab [macrophage inflammatory protein (MIP)-8a], respectively, three times a week for 29 weeks, after being injected once intraperitoneally with 0·5 ml pristane. In the second experiment, antibody injection started after the onset of nephritis and was carried out for 2 months, with similar groups as described above. MIP-8a improved proteinuria, decreased the amounts of glomerular injury markers, serum interleukin (IL)-6, IL-1 and monocyte chemoattractant protein (MCP)-1, and F4/80 macrophages in the interstitium and glomeruli, in both experiments. When MIP-8a was used as early intervention, a decrease in mouse serum anti-nuclear antibody (ANA) titres and reduced deposition of immunoglobulins in glomeruli were observed. This effect was associated with reduced serum titres of immunoglobulin (Ig)G2a but not IgG1, IgG2b and IgG3. Furthermore, pathological analysis showed lower glomerular activity index and less fibronectin in MIP-8a treated mice. This study suggests that FcαRI targeting could halt disease progression and lupus activation by selective inhibition of cytokine production, leucocyte recruitment and renal inflammation. Our findings provide a basis for the use of FcαRI as a molecular target for the treatment of lupus.

Detoxification mechanism of asbestos materials by microwave treatment.

The detoxification mechanism of asbestos materials was investigated through simulations and experiments. The permittivities of pure CaO and Mg3Si4O12, as quasi-asbestos materials, were measured using the cavity perturbation method. The real and imaginary parts of the relative permittivity (ɛr' and ɛr″) of CaO are functions of temperature, and numerical simulations revealed the thermal distributions in an electromagnetic field with respect to both asbestos shape and material configuration based on permittivity. Optical microscopic observation revealed that the thickness of chrysotile fibers decreased as a result of CaO heating. The heating mechanism of asbestos materials has been determined using CaO phase, and the detoxification mechanism of asbestos materials was discussed based on the heating mechanism.

On the genesis of heterogeneous photocatalysis: a brief historical perspective in the period 1910 to the mid-1980s.

The concept Photocatalysis and, of greater import here, Heterogeneous Photocatalysis were first introduced in the second decade (1910-1920) of the 20th century according to the CAPLUS and MEDLINE databases (SciFinder). This review reports a brief historical perspective on the origins of the two concepts, whether implied or explicitly stated, in some detail up to about the mid-1980s when heterogeneous photocatalysis witnessed the beginning of an exponential growth, with particular emphasis on the use of nanosized TiO(2) particles in powdered form as the (so-called) photocatalyst of choice in environmental applications because of its inherent properties of abundance and chemical stability in acidic and alkaline aqueous media (in the dark), in contrast to ZnO that had been the metal oxide of choice in the early days. The early workers in this area often used the term photosensitization rather than the current popular term photocatalysis, used since the early 1980s. The term Photocatalysis appeared in the literature as early as 1910 in a book by Plotnikow (Russia) and a few years later it was introduced in France by Landau. The review also reports on contributions during the early years by Terenin at the University of St. Petersburg (previously Leningrad, Soviet Union), and in the decade spanning 1975-1985 contributions by Bard's group at the University of Texas at Austin (USA) as well as those of other groups. Some activities into the conversion of light energy to chemical fuels (e.g. H(2)) during the 1975-1985 decade are also considered.

Negative regulation of inflammatory responses by immunoglobulin A receptor (FcαRI) inhibits the development of Toll-like receptor-9 signalling-accelerated glomerulonephritis.

Myeloid FcαRI, a receptor for immunoglobulin (Ig)A, mediates cell activation or inhibition depending on the type of ligand interaction, which can be either multivalent or monovalent. Anti-inflammatory signalling is triggered by monomeric targeting using anti-FcαRI Fab or IgA ligand binding, which inhibits immune and non-immune-mediated renal inflammation. The participation of Toll-like receptors (TLRs) in kidney pathology in experimental models and various forms of human glomerular nephritis has been discussed. However, little is known about negative regulation of innate-immune activation. In the present study, we generated new transgenic mice that express FcαRI(R209L) /FcRγ chimeric protein and showed that the monovalent targeting of FcαRI exhibited inhibitory effects in an in vivo model of TLR-9 signalling-accelerated nephritis. Mouse monoclonal anti-FcαRI MIP8a Fab improved urinary protein levels and reduced the number of macrophages and immunoglobulin deposition in the glomeruli. Monovalent targeting using MIP8a Fab attenuates the TLR-9 signalling pathway and is associated with phosphorylation of extracellular signal-related protein kinases [extracellular signal-regulated kinase (ERK), P38, c-Jun N-terminal kinase (JNK)] and the activation of nuclear factor (NF)-κB. The inhibitory mechanism involves recruitment of tyrosine phosphatase Src homology 2 domain-containing phosphatase-1 (SHP-1) to FcαRI. Furthermore, cell transfer studies with macrophages pretreated with MIP8a Fab showed that blockade of FcαRI signalling in macrophages prevents the development of TLR-9 signalling-accelerated nephritis. These results suggest a role of anti-FcαRI Fab as a negative regulator in controlling the magnitude of the innate immune response and a new type of anti-inflammatory drug for treatment of kidney disease.

Significance of glomerular activation of the alternative pathway and lectin pathway in lupus nephritis.

The objective of the present study was to elucidate the association between glomerular complement depositions belonging to the alternative (AP) and lectin (LP) pathways, and clinical findings of lupus nephritis (LN). Immunofluorescence (IF) was performed on 17 LN patients using antibodies against factor B, factor H, properdin, mannose-binding lectin (MBL) and L-ficolin. Compared with factor B/factor H negative patients (n = 9), positive patients (n = 8) showed longer duration of LN (p < 0.05) and more severe interstitial fibrosis (p < 0.05). Eleven patients had properdin deposition in glomeruli, and in three of them, with a duration of LN of less than 1 month, factor B was undetectable. Compared with properdin negative patients (n = 6), positive patients (n = 11) showed significantly higher urinary protein excretion (p < 0.01). MBL/L-ficolin positive patients (n = 11) also had significantly higher urinary protein excretion (p < 0.05) compared with negative patients (n = 6). An independent association was found between glomerular deposition of properdin and that of MBL/L-ficolin (p < 0.01) in addition to factor B/factor H. Traces of glomerular activation of AP and LP reflected the clinical status of LN. It appears that glomerular deposition of each complement component, especially properdin, may be an index of the histological activity of LN.

Type B insulin resistance syndrome with systemic lupus erythematosus.

Type B insulin resistance syndrome is a rare disease. Auto-antibodies to the insulin receptor frequently appear in the case of systemic lupus erythematosus (SLE). We report herein a case of a 56-year-old man who had presented discoid skin lesions since 1990. He was admitted to the hospital because of unconsciousness and severe hypoglycemia in 2006, and was diagnosed as having Type B insulin resistance syndrome with the presence of insulin receptor antibody. He had frequently repeated hypoglycemic and hyperglycemic episodes in spite of treatment with prednisolone (5 - 10 mg/day), and mild proteinuria of 1.5 g/day was observed. His laboratory findings on admission revealed pancytopenia and positive titer for antinuclear antibody (ANA). From these findings and his past history of skin lesions, we diagnosed him as SLE. We performed renal biopsy and his histological diagnosis was lupus nephritis Class 5 with the findings of podocytic shedding. Prednisolone dosage was increased from 10 to 60 mg/day. Thereafter, his glucose metabolism improved and proteinuria disappeared. The dose of prednisolone was tapered to 30 mg/day without recurrence of hypoglycemia and proteinuria. Early treatment with prednisolone might ameliorate proteinuria and insulin resistance. We experienced a rare case of Type B insulin resistance syndrome with increased activity of SLE, complicated with lupus nephritis. It appears that Type B insulin resistance syndrome should be suspected in differential diagnosis of hypoglycemia in SLE patients.

Long-term effects of the oral adsorbent, AST-120, in patients with chronic renal failure.

The oral adsorbent AST-120 has been widely used in Japan to delay the initiation of dialysis therapy in patients with chronic renal failure. This study evaluated the long-term effects of AST-120 in patients with chronic renal failure who had not previously undergone dialysis. One hundred out-patients were prospectively enrolled and prescribed 6 g/day oral AST-120 for >or= 1 year. The clinical effectiveness of AST-120 was evaluated by comparing changes in the slope of the reciprocal serum creatinine-time plot (1/sCr slope) before and after AST-120 administration. The 1/sCr slope improved significantly after >or= 1 year of AST-120 treatment and greatest improvement was observed in patients with the longest AST-120 administration period (> 30 months). The results suggest that long-term treatment with AST-120 may be beneficial for chronic renal failure patients in the pre-dialysis stage.

Tubular epithelial cells have the capacity to transdifferentiate into CD68-positive macrophage-like cells by oxidative stress.

OBJECTIVE: The present study was intended to assess transdifferentiation from tubular epithelial cells to macrophage- like cells. METHODS: Puromycin aminonucleoside nephrotic rats were sacrificed at days 4, 8, 24 and 112. We immunohistochemically evaluated CD68, CD163, and cytokeratin AE1/AE3, known as markers for macrophages and tubular epithelial cells. Nitrotyrosine, gp91(phox) and Rac 1 expressions was also analyzed. CD68 expression in cultured murine proximal tubular epithelial cells (mProx) stimulated by crude and pure BSA was examined by flow cytometry and immunofluorescence. RESULTS: The tubular CD68-positive cells were observed on day 112. Immunoelectronmicroscopy revealed that some CD68-positive cells showed brush borders on the cell membrane and some of cytokeratin-positive tubular cells also expressed CD163 in mirror sections. The tubular CD68-positive cells were also positive for nitrotyrosine, gp91 (phox) and Rac 1. They contained lipid in their cytoplasm. Crude BSA, containing free fatty acid, induced CD68 expression in a dose- and time-dependent manner in mProx, but not pure BSA. The surface expression of CD68 was increased by high dose and long term stimulation with crude BSA as shown by immunofluorescence. CONCLUSIONS: We confirmed that tubular epithelial cells have the capacity to transdifferentiate to CD68-positive macrophage-like cells, which may be linked to oxidative stress.

Improvement of peritoneal calcification after parathyroidectomy in a peritoneal dialysis patient.

Peritoneal calcification is one of the complications of peritoneal dialysis (PD). It can become serious, leading to severe abdominal pain and even death. Possible mediators of peritoneal calcification in PD patients are assumed to include acetate buffer, overdosage of vitamin D, repeated peritonitis, hypertonic dialysate, calciphylaxis and secondary hyperparathyroidism (SHPT). However, the mechanism and treatment of peritoneal calcification are controversial. Few reports have appeared on improvement of peritoneal calcification after parathyroidectomy (PTX) for SHPT of long duration. We report herein the case of a 48-year-old man on dialysis for 17 years including PD for 14 years. In 1989, he was admitted to hospital because of end-stage renal disease (ESRD), and started treatment with PD. Abdominal computed tomography (CT) first showed peritoneal calcification in August 2002. Peritoneal calcification did not improve despite conventional treatment including discontinuation of PD, control of calcium phosphate product to less than 55 mg2/dl2, removal of the peritoneal catheter and empirical prednisolone (PSL) usage. The intact parathyroid hormone (i-PTH) level was increased over 1,000 pg/ml and extra-osseous calcification occurred. Total PTX was performed in November 2004. Postoperatively, the i-PTH level decreased immediately and calcium phosphate product was maintained in the reference range. Abdominal CT after PTX showed improvement of peritoneal calcification in September 2005. It appeared that PTX could be used to treat patients with persistent peritoneal calcification not responding to conventional treatment. It was postulated that SHPT might play a crucial role in accelerating peritoneal calcification in PD patients.

Possible involvement of mast cells in renal fibrosis in patients with IgA nephropathy.

OBJECTIVE: The objective of the present study is to investigate whether human mast cells (MC) contribute to renal damage through local activation of the renin-angiotensin system, by assessing their numbers in renal biopsy specimens from patients with IgA nephropathy (IgAN) or minimal change nephrotic syndrome (MCNS). METHODS: In patients with IgAN and MCNS, the numbers of tryptase-positive MC (MC(T)) and MC positive for both tryptase and chymase (MC(TC)) were examined histopathologically. Serum creatinine level, mean blood pressure and the severity of glomerular and tubulointerstitial lesions were also determined. RESULTS: MC(TC) numbers differed between IgAN patients and MCNS patients. IgAN patients had more MC(TC) than MC(T). MC were found around but not in the conglomerate of the AngiotensinII (AngII)-positive cells. In the IgAN patients with the most severe pathology, the number of AngII-positive cells was correlated with that of MC(TC) and MC(T). CONCLUSION: Chymase-dependent AngII synthesis due to human MC may be involved in the inflammatory and fibrotic processes of IgAN.

Th1 polarization in murine IgA nephropathy directed by bone marrow-derived cells.

IgA nephropathy is the most common form of progressive glomerulonephritis although the pathophysiology of this nephropathy is unclear. The ddY mouse is a spontaneous animal model with variable incidence and extent of glomerular injury mimicking human IgA nephropathy. Here, we transplanted bone marrow cells from 20-week-old ddY mice with beginning or quiescent IgA nephropathy into irradiated similar ddY mice, C57Bl/6 (Th1 prone) mice, or BALB/c (Th2 prone) mice. Serum IgA/IgG complex and Th1/Th2 polarization of spleen cells was determined by enzyme-linked immunosorbent assay and confirmed by fluorescent cytometric analysis. The ddY mice with commencing IgA nephropathy demonstrated strong polarization toward Th1, while those with quiescent disease were Th2 polarized. Serum levels of IgA/IgG2a immune complex significantly correlated with the severity of the glomerular lesions. Bone marrow taken from mice with commencing IgA nephropathy conferred IgA nephropathy with Th1 polarization in recipient-quiescent mice, while transplantation from the quiescent mice ablated glomerular injury and mesangial IgA/IgG deposition in those commencing IgA disease. However, adoptive transfer of CD4(+) T cells from those whose disease began failed to induce any IgA deposition or renal injury. Our study suggests that bone marrow cells, presuming IgA producing cells, may initiate this disease. Th1 cells may be involved in the pathophysiology of the disease after glomerular IgA deposition.

Dose-response to a jelly preparation of calcium polystyrene sulfonate in patients with hyperkalemia--changes in serum potassium levels with or without a RAAS inhibitor.

AIMS: In this study, dose-response of the serum potassium-lowering effect of a calcium polystyrene sulfonate (PS) preparation was investigated. Changes in the serum potassium level were also examined with or without application of a RAAS inhibitor, which is said to increase the serum potassium level. SUBJECTS AND METHODS: 23 patients diagnosed to have hyperkalemia associated with chronic renal failure were enrolled in this study. The study drug, a PS-Ca jelly preparation (Argamate jelly), was started at a daily dose of 1 preparation (5 g as PS-Ca), and the dose was increased by 1 preparation every month to finally reach 3 preparations per day. Blood samples were collected once a month and serum levels of creatinine and electrolytes were measured. RESULTS: PS-Ca jelly decreased serum potassium levels in a dose-dependent manner. Decreases were 0.67 mEq/l at 5 g of PS-Ca/day, 1.06 mEq/l at 10 g/d, and 1.33 mEq/l at 15 g/d. Irrespective of the use of the RAAS inhibitor, serum potassium levels decreased significantly in a dose-dependent manner. Furthermore, no major change in serum creatinine levels occurred in subjects in which the RAAS inhibitor was used, although in subjects in which the RAAS inhibitor was not used, serum creatinine level tended to gradually increase. CONCLUSION: Serum potassium levels were reduced in a dose-dependent manner by administration of 5-15 g/d of PS-Ca, and it appeared that together with control of serum potassium levels, renal function should be maintained by continuous administration of RAAS inhibitor.

Effect of educational hospitalization on chronic kidney disease (CKD) patients.

UNLABELLED: Although dietary control is recommended to chronic kidney disease (CKD) patients, improvement of compliance and education of outpatients are very difficult. The purposes of the present study are to estimate the dietary intake of sodium (Na) and protein by measuring urinary Na and urea nitrogen (UN) excretion, and to evaluate the efficacy of educational hospitalization. METHODS: 70 patients (41 men and 29 women) with a mean age of 58.7+/-15.8 years participated in the present study. Most patients had chronic kidney disease (CKD, Stage 3 or 4). Patients were hospitalized to learn about their diseases and dietary restrictions for 1 week. Patients were given low salt (less than 6 g/day) and low protein (0.6-1.0 g/standard body weight kg/day) diet. 24-hour urine samples were collected at the start (Day 2) and on completion (Day 7) of hospitalization. Salt and protein intakes were estimated using patients' 24-hour urine samples. RESULTS: Estimated salt intake was significantly decreased on completion of the hospitalization (Day 7) (p < 0.05). Estimated protein intake was also decreased slightly, but this was not statistically significant. There were significant differences in the changes of body weight, body mass index (BMI), and systolic and diastolic blood pressure between the start (Day 2) and completion (Day 7) of hospitalization. 89% of the patients showed an improved blood pressure without changes of antihypertensive drugs. CONCLUSIONS: It appears that short-term hospitalization is an effective program for achieving dietary and blood pressure control in CKD patients.

Minor gene effect of leptin receptor variant on the body weight in KK/Ta mice.

OBJECTIVE: Leptin is an adipocyte-derived hormone involved in body weight regulation that acts through the leptin receptor. Previous studies exploring potential association between the leptin receptor (Lepr) variant and obesity have reported conflicting results. The objectives of the present study are to evaluate (1) whether the Lepr variant contributes to type 2 diabetes and its related disorders such as obesity and (2) whether the gene interaction between Lepr and Zn-alpha(2) glycoprotein1 (Azgp1) genes is recognized using genetically homogeneous type 2 diabetic KK/Ta mice. METHODS: The levels of leptin (Lep) and Lepr mRNA in adipose tissues and brain were measured by relative quantitative RT-PCR. The levels of leptin protein in sera were measured by enzyme-linked immunosorbent assay. Genotyping of backcross mice was performed using a mismatch primer. RESULTS: Leptin protein and its mRNA levels were increased in KK/Ta mice. Lepr mRNA levels of KK/Ta mice did not differ from those of BALB/c mice. Sequence analysis revealed that the coding region of Lep in KK/Ta mice was identical to that in BALB/c mice. Six nucleotide polymorphisms were observed in the coding region of Lepr. In KK/Ta x (BALB/c x KK/Ta) F1 backcross mice, the Lepr variant of KK/Ta mice failed to alter any of the variables of obesity except for body weight at 20 weeks of age. However, it enhanced the effect of Azgp1 on body weight. CONCLUSION: It is concluded that the Lepr variant contributes to obesity to some degree in KK/Ta mice.

Monocyte chemoattractant protein (MCP)-1 production via functionally reconstituted Fcalpha receptor (CD89) on glomerular mesangial cells.

BACKGROUND: Fc alpha receptor (FcalphaR; CD89) is the receptor for Fc portion of IgA in various cells, and displays various immunological responses on binding. It is important to analyze the mesangial functions via FcalphaR in the pathogenesis of IgA nephropathy. However, it is still controversial whether FcalphaR is expressed on mesangial cells. To assess biological functions of FcalphaR on the mesangial cells, we established mesangial transfectants that expressed FcalphaR with or without FcRgamma chain that is a common signaling molecule of FcRs. The production of monocyte chemoattractant protein-1 (MCP-1) by mesangial cells is known to contribute to cellular infiltration into glomeruli and subsequent glomerular injuries. METHODS: Murine mesangial cell lines (SV40 MES 13) were transfected with cDNA of the human FcalphaR. Furthermore, we co-transfected some of the FcalphaR transfectants with cDNA of human FcRgamma chain. The tyrosine phosphorylation of the intra-mesangial proteins after FcalphaR cross-linking was examined by immunoprecipitation. MCP-1 production from each transfectant stimulated with heat aggregated IgA was determined by sandwich ELISA. RESULTS: Two kinds of mesangial transfectants stably expressed human FcalphaR with or without FcRgamma chain (FcalphaR(+), FcalphaR(+)/gamma(+)). Phosphorylation of FcRgamma chain and syk kinase was detected in FcalphaR(+) and FcalphaR(+)/gamma(+) cells, but not in untransfected cells. Aggregated IgA induced significantly higher MCP-1 production in FcalphaR(+)/gamma(+) than those in FcalphaR(+) or untransfected control. CONCLUSIONS: Present study demonstrated that FcalphaR and FcRgamma chain could be reconstituted in mesangial cells and mediated MCP-1 production by aggregated IgA in a dose-dependent manner. Current data would argue that FcalphaR can be activated in mesangial cells through their own machinery, although underlying mechanisms for FcalphaR induction in mesangial cells remain unclear.

Protein localization and mRNA expression of epimorphin in mouse and human kidneys.

Epimorphin is a mesenchymal cell surface protein which induces epithelial branching morphogenesis. However, the role of epimorphin in the kidney has not been addressed. In the present study, the localization of epimorphin protein and the expression of its mRNA were investigated in the developing mouse and adult human kidneys using immunohistochemistry and semiquantitative RT-PCR. The in vitro expression of epimorphin protein and its mRNA was also explored in cultured mouse and human mesangial cells. Epimorphin protein was expressed in the renal interstitium and the circumference of the comma-shaped body at day 16 of gestation. The intensity and distribution of epimorphin were gradually increased during kidney differentiation and maturation. Epimorphin was first observed in glomeruli at 1 week of age. The localization of epimorphin in glomerular mesangial cells and interstitial fibroblasts was confirmed by immunoelectron microscopy of 2-week-old mouse kidneys. The highest mRNA expression of epimorphin was observed at day 16 of gestation, thereafter it diminished with the maturation of the kidney. A similar localization of epimorphin was observed in a normal adult human kidney. Cultured human mesangial cells expressed epimorphin mRNA 150-kD protein. These results suggest that epimorphin may play a role in the development of the kidney and in the differentiation of fibroblast and mesangial cells.

Relationship between mast cells in the tubulointerstitium and prognosis of patients with IgA nephropathy.

There have been a few reports suggesting that mast cells may play an important role in the development of fibrosis and/or the degradation of extracellular matrix. We examined the relationship between the number of distribution of mast cells in tubulointerstitium and prognosis of patients with IgA nephropathy. Renal biopsy specimens were stained with mouse monoclonal antihuman mast cell tryptase antibody and then with aniline blue. Specimens from 45 patients with IgA nephropathy and from 5 patients with minimal-change nephrotic syndrome were used. There was a significant correlation between the number of mast cells per unit area of the whole tubulointerstitium and the degree of tubulointerstitial fibrosis or renal function. Patients with IgA nephropathy were divided into two groups (group 1: 'minimal' and 'slight'; group 2: 'moderate' and 'advanced') according to the classification by a previously reported method. Mast cells were mainly observed in the fibrotic areas in group 1. In group 2, many mast cells were detected not only in the fibrotic but also in the nonfibrotic areas. It appears that the number of mast cells in the nonfibrotic areas may be one of the predictive factors for the prognosis of patients with IgA nephropathy.

Effect of steroid-liposome on immunohistopathology of IgA nephropathy in ddY mice.

Immunopathological studies were performed to determine whether glomerular injuries in ddY mice, a spontaneous animal model for IgA nephropathy, are influenced by treatment with a newly developed liposome loaded with prednisolone phosphate (PSL-liposome). The newly synthesized novel cationic lipid 3,6-dipentadeciroxy-1-amizino-benzene (TRX-20) was employed to obtain selective affinity to the anionic cell surface and extracellular matrices in glomerular mesangial lesions. ddY mice were treated intravenously with 1.0 mg/kg of PSL-liposome once a week for 16 weeks (from 45 weeks to 61 weeks of age). ddY mice were also intravenously treated with 1.0 mg/kg of ordinary PSL once a week for the same duration. On immunofluorescence, depositions of IgA and C3 in the glomerular mesangial areas and capillary walls of PSL-liposome-treated ddY mice were markedly decreased as compared with those of ordinary PSL-treated and untreated control ddY mice. The mean intensity of IgA and C3 in glomeruli of PSL-liposome-treated ddY mice was decreased as compared with that in ordinary PSL-treated and untreated control ddY mice. Glomerular mesangial expansion in PSL-liposome-treated ddY mice was milder than that found in ordinary PSL-treated ddY mice or untreated control ddY mice. It appears that treatment with PSL-liposome is effective in improving glomerular IgA and C3 depositions and glomerular expansion in IgA nephropathy of ddY mice.