Evidence of lectin complement pathway activation in poststreptococcal glomerulonephritis.
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Adolescent↗
Biomedical subjects
I Ohsawa
Publications and source records attributed to I Ohsawa.
Complement activation accelerates glomerular injury in diabetic rats.
A known inhibitor of the complement cascade (K-76 COONa) was administered to an inbred diabetic rat model to investigate whether the complement system may play a role in the progression of diabetic glomerulosclerosis. Drinking water containing K-76 COONa was available continuously to inbred diabetic rats (Otsuka Long-Evans Tokushima Fatty, OLETF) from the age of 25 to 55 weeks (Group L). Drinking water without K-76 COONa was similarly available to OLETF rats (Group H) and nondiabetic control rats (Long-Evans Tokushima Otsuka, LETO) (Group C). The levels of plasma glucose (mg/dl) at the 55th week were 156 +/- 16 in Group C, 252 +/- 18 in Group L and 349 +/- 93 in Group H. There was no significant difference in the degree of diabetes between Group L and Group H. The levels of urinary protein at 55 weeks of age (mg/day) were 2.1 +/- 0.4 in Group C, 11. 6 +/- 1.5 in Group L and 18.0 +/- 2.8 in Group H. The level of urinary protein was significantly decreased by the administration of K-76 COONa. Histological examination of renal specimens from the sacrificed rats at 55 weeks of age revealed diffuse mesangial expansion in almost all glomeruli in Group H, exudative lesions in 30% of glomeruli in Group H, and only mild mesangial expansion was recognized in Group L. Immunofluorescence study revealed brilliant staining of C3 and immunoglobulins (Ig) in Group H; trace staining of Ig and no staining of C3 were recognized in Group L. The incubation study with guinea pig serum and glomeruli from rats revealed that Ig and complement components also bound to injured glomeruli in vitro. These data indicate that the complement cascade is activated by injured glomeruli and this activation exacerbates diabetic glomerulosclerosis.
Animals↗
High prevalence of hepatitis C virus antibodies in older patients with membranoproliferative glomerulonephritis.
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Adolescent↗
Troglitazone improves insulin-stimulated glucose utilization associated with an increased muscle glycogen content in obese Zucker rats.
Recent studies have demonstrated that troglitazone has the capacity to improve insulin resistance. The present study was undertaken to determine the effect of troglitazone on in vivo insulin action, the activities of the pyruvate dehydrogenase (PDH) complex and 3-hydroxyacyl-CoA dehydrogenase (3-HADH) in muscle, and muscle GLUT-4 and glycogen content in obese and lean Zucker rats. Rats were fed a normal chow diet with and without troglitazone as a food admixture (0.2%) for 3 weeks. In vivo insulin action was measured by the sequential euglycemic clamp technique at two different insulin infusion rates (6 and 30 mU/kg BW/min). At the basal (fasting) state and after the clamp studies, the activities of PDH complex and 3-HADH, and the amounts of GLUT-4 and glycogen contained in the red gastrocnemius muscles were determined. Troglitazone treatment produced a significant rise in the metabolic clearance rate of glucose (MCR) during the 6-mU/kg BW/min insulin clamp study (19.5+/-3.9 vs 9.9+/-1.5 ml/kg BW/min, mean+/-SE, P<0.05) in obese rats, but not in lean rats. Troglitazone significantly increased the muscle glycogen content after the clamp study, compared to non-treated rats, in obese rats (9.9+/-0.5 vs 6.5+/-0.4 mg/g tissue, P<0.05) and has the tendency to increase the activity state of PDH complex in obese and lean rats at the fasting state. However, no effect of the drug on muscle GLUT-4 content was found. These results indicate that troglitazone may improve insulin sensitivity associated with increased muscle glycogen content.
3-Hydroxyacyl CoA Dehydrogenases↗
Relationship between insulin and blood pressure in Japanese obese subjects.
OBJECT: The association of obesity and hypertension is well recognized. However, the nature of the relationship between increased body weight and blood pressure (BP) elevation has remained obscure. PATIENTS AND METHODS: We evaluated BP, insulin sensitivity, insulin clearance and fasting plasma insulin concentration in 19 younger (over 40 years) and in 15 older (more than 40 years) obese subjects to determine the relationships between BP and other factors. Insulin sensitivity and clearance were determined with the euglycemic clamp technique. RESULTS: BP was not associated with insulin sensitivity although most of the subjects showed insulin resistance. In the younger obese group, a positive correlation between diastolic BP and body mass index (kg/m2) was found (r=0.740; p=0.043). In the older obese group, systolic and diastolic BP were correlated with fasting plasma insulin levels (r=0.705; p=0.003; r=0.574; p=0.025, respectively), and systolic BP was inversely correlated with insulin clearance (r=-0.715, p=0.003). CONCLUSION: These results suggest that insulin is an important factor in BP elevation in older obese subjects, but not in younger obese subjects.
Adolescent↗
Inhibitory effect of free sialic acid on complement activation and its significance in hypocomplementemic glomerulonephritis.
The role of free sialic acid on complement activation was investigated. The serum levels of free sialic acid and total sialic acid were measured by previously described methods in 16 patients with acute post-infectious glomerulonephritis (AGN), 27 patients with systemic lupus erythematosus (SLE), 15 patients with persistent hypocomplementemic membranoproliferative glomerulonephritis (MPGN), and 13 healthy controls. A statistical study demonstrated an increased level of free sialic acid in patients with AGN and SLE in which the hypocomplementemia improved throughout the course and a decreased level of free sialic acid in patients with MPGN and SLE in which hypocomplementemia continued throughout the course. The levels of total sialic acid were significantly increased in patients with AGN and SLE and were significantly decreased in patients with MPGN. There was no correlation between the levels of free sialic acid and total sialic acid in patients with AGN, in whom the levels of both total and free sialic acids were increased. To examine the effect of free sialic acid on the complement cascade, lipopolysaccharide (LPS) was incubated with normal human serum (NHS) in the various concentrations of N-acetyl neuraminic acid (NANA), a member of the sialic acid group. The incubation mixtures were examined by enzyme immunoassay using monoclonal anti-iC3b antibody or anti-Bb antibody. Native C3 or Factor B in NHS broke down less following the addition of NANA. To elucidate the role of NANA on the hemolytic function of C3, a rabbit erythrocyte (Ra E) hemolytic assay was carried out. Ra E lysed completely in the presence of R3 with native C3. However, hemolysis occurred to a lesser degree in C3-depleted serum (R3) or R3 with NANA-treated C3. To investigate the influence of NANA on complement components, the levels of complement components were measured in the incubation mixture with various doses of NANA and NHS. The levels of C3 and C5 were significantly decreased after the addition of NANA, even though the levels of Factor H and Factor I were not markedly changed. These data indicate that NANA exerts an influence on the complement components even though it has no effect on the regulatory proteins of complement. Our in vitro findings, together with the in vivo data, suggest that free sialic acid might have an inhibitory effect on the activation of C3 and the following complement cascade, and might also have been responsible for the improvement of hypocomplementemia.
Animals↗
[Three cases of pregnancy in primary glomerulonephritis with successful outcomes in spite of severe histological findings].
When women with kidney disease wish to have children, concerns are raised about the adverse effect on their renal function. Although the situation is less clear in regard to the effects, there is general agreement that a moderately severe decrease in renal function, especially in the presence of significant hypertension, reduces the chance of conception, and a successful outcome of gestation. On the other hand, several reports maintain that in most patients, pregnancy does not change the natural history of glomerular disease. Accordingly, we reported successful cases in whom renal function remained preserved. The three cases suffered from different types of glomerulonephritis (GN) and percutaneous renal biopsies were conducted before pregnancy. All biopsy specimens were examined by light and immunofluorescence microscopy, and were diagnosed as IgA nephropathy, sclerosing GN and membranoproliferative GN, respectively. Since severe histological findings were found and their data worsened (serum creatinine > 1.3 mg/dl, 24-hr creatinine clearance < 70 ml/min), their chance of having children appeared low. However, as we did not observe deterioration of clinical findings and hypertension over the ten-year follow-up, we allowed conception resulting in the birth of normal children. Thus we should mention the relatively favourable courses of nephropathy in some patients with GN, particularly in patients with stable renal disease and normal blood pressure, it should not be considered an indication for termination. It is important to observe the status of glomerular disease for as long as possible.
Adult↗
Novel domain-specific actions of amyloid precursor protein on developing synapses.
The effect of the secretory form of amyloid precursor protein (sAPP) on synaptic transmission was examined by using developing neuromuscular synapses in Xenopus cell cultures. The frequency of spontaneous postsynaptic currents (SSCs) was reduced by the addition of sAPP, whereas the amplitude of impulse-evoked postsynaptic currents (ESCs) was increased by sAPP. These opposing effects on spontaneous versus evoked release were separated by using the specific domain of APP. The C-terminal fragment of sAPP (CAPP) only reduced SSC frequency and did not affect ESCs. By contrast, the N-terminal fragment of sAPP (NAPP) did not affect SSC frequency but did increase ESC amplitude. The reduction of SSC frequency by sAPP appears to be mediated by activation of potassium channels through a cGMP-dependent pathway, whereas the increase of ESC amplitude is mediated by a different pathway involving activation of protein kinase(s). These results suggest the potential role of sAPP as a modulator of synaptic activity by two specific domains.
8-Bromo Cyclic Adenosine Monophosphate↗
Involvement of amyloid precursor protein in functional synapse formation in cultured hippocampal neurons.
Amyloid precursor protein (APP) is known to be widely expressed in neuronal cells, and enriched in the central and peripheral synaptic sites. Although it has been proposed that APP functions in synaptogenesis, no direct evidence has yet been reported. In this study we investigated the involvement of APP in functional synapse formation by monitoring spontaneous oscillations of intracellular Ca2+ concentration ([Ca2+]i) in cultured hippocampal neurons. As more and more neurons form synapses with each other during the culture period, increasing numbers of neuronal cells show synchronized spontaneous oscillations of [Ca2+]i. The number of neurons that showed synchronized spontaneous oscillations of [Ca2+]i was significantly lower when cultured in the presence of monoclonal antibody 22C11 against the N-terminal portion of APP. Moreover, incubation with excess amounts of the secretory form of APP or the N-terminal fragment of APP also inhibited the increase in number of neurons with synchronized spontaneous oscillations of [Ca2+]i. The addition of monoclonal antibody 22C11 or secretory form of APP did not, however, affect MAP-2-positive neurite outgrowth. These findings suggest that APP play a role in functional synapse formation during CNS development.
Amyloid beta-Protein Precursor↗
Secreted form of beta-amyloid precursor protein activates protein kinase C and phospholipase Cgamma1 in cultured embryonic rat neocortical cells.
The secreted form of beta-amyloid precursor protein (sAPP) has been reported to exert various biological activities in cultured neurons. The signal transduction mechanisms underlying these physiological functions of sAPP remain unclear. We now report that treatment of neural cells with the secreted form of APP695 (sAPP695) leads to dose- and time-dependent increase in phosphorylation of the endogenous substrates with a molecular mass of 80, 57 and 43 kDa. Pretreatment of cells with protein kinase C (PKC) inhibitor H-7 reduced phosphorylation of the 80- and 43-kDa proteins in a dose-dependent manner. The effect of sAPP695 on the phosphorylation is mimicked by phorbol 12-myristate-13-acetate (PMA). Downregulation of PKC by prolonged treatment of cells with PMA abolished sAPP695-enhanced phosphorylation of the 80- and 43-kDa proteins, indicating PKC is involved in the sAPP695-enhanced phosphorylation of these proteins in the cells. We also suggest that the 80- and 43-kDa proteins phosphorylated by sAPP695-stimulation are the major PKC substrates myristoylated alanine-rich C-kinase substrate and growth-associated protein-43. Furthermore, we demonstrate that tyrosine phosphorylation of phospholipase Cgamma1 and formation of inositol 1,4,5-trisphosphate were increased by sAPP695-stimulation. These observations suggest that sAPP695 induces the activation of the signaling pathways through a stimulation of phosphoinositide-PKC cascade.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
The effect of a secreted form of beta-amyloid-precursor protein on intracellular Ca2+ increase in rat cultured hippocampal neurones.
1. The effects of secreted forms of beta-amyloid-precursor proteins (APP(S)s) on the intracellular Ca2+ concentration ([Ca2+]i) were investigated in rat cultured hippocampal neurones. APP695S, a secretory form of APP695, attenuated the increase in [Ca2+]i evoked by glutamate. In addition, APP695S itself evoked an increase in [Ca2+]i in 1 or 2 day-cultured hippocampal cells, but not in 7 to 13 day-cultured cells. 2. Eighty-one percent of neurones which were immunocytochemically positive for microtubule-associated protein 2 responded to APP695S with an increase in [Ca2+]i. 3. APP695S induced a transient rise in [Ca2+]i even in the absence of extracellular Ca2+ and produced an elevation in inositol-1,4,5-trisphosphate (IP3) in a concentration-dependent manner from 100 to 500 ng ml(-1). In the presence of extracellular Ca2+, APP695S caused a transient rise in [Ca2+]i followed by a sustained phase at high [Ca2+]i, suggesting Ca2+ entry from the extracellular space. 4. The [Ca2+]i elevation was mimicked by amino terminal peptides of APPs, but not by carboxy terminal peptides. 5. These results taken together suggest that APP695S induces an increase in [Ca2+]i in hippocampal neurones through an IP3-dependent mechanism that changes according to the stage of development.
Amyloid beta-Protein Precursor↗
Effect of insulin on intramuscular 3-hydroxybutyrate levels in diabetic rats.
It has been shown that inhibition of lipolysis and ketogenesis by insulin is more sensitive than suppression of hepatic glucose production and stimulation of tissue glucose uptake. Clinically, on the other hand, blood glucose concentrations fall much more quickly than blood ketone concentrations. Therefore, during continuous insulin infusion at a rate of 3.0 mU/kg B.W./min over a period of 150 min we monitored blood glucose and 3-hydroxybutyrate (3-OHBA) concentrations and muscle 3-OHBA levels using the microdialysis technique in streptozotocin-induced diabetic rats. Blood glucose concentrations decreased rapidly after insulin infusion. However, significant reduction in blood-3-OHBA concentration was found for the last 30 min. In muscle dialysate 3-OHBA concentrations and muscle local blood flow there was no significant change throughout the study. These results suggest that one possible mechanism of delayed improvement in ketonemia is a reduction in muscle removal capacity.
3-Hydroxybutyric Acid↗
Glomerular deposition of mannose-binding lectin (MBL) indicates a novel mechanism of complement activation in IgA nephropathy.
BACKGROUND: IgA nephropathy (IgA-N) is considered the most common glomerular disease in the world and leads to renal failure in a substantial number of patients. Although many studies have looked at the pathogenesis of the disease, many points need to be clarified, including the mechanism of complement activation. Recent studies have shown that mannose-binding lectin (MBL or mannose binding protein, MBP) initiates activation of the complement cascade (lectin pathway) utilizing two types of MBP-associated serine protease, namely MASP-1 and MASP-2. The present study was undertaken to elucidate whether the lectin pathway was involved in the pathogenic mechanism of IgA-N. METHODS: Forty-five renal biopsy cases with IgA-N, 35 cases with other forms of glomerulonephritis (GN), and normal kidney tissues were collected and an immunohistochemical study was performed using monoclonal antibodies against MBL and MASP-1. Furthermore, clinicopathological and serological features were also analysed in the patients with IgA-N. RESULTS: Glomerular deposition of MBL, which was accompanied by MASP-1, was detected in 11 of 45 (24.4%) cases with IgA-N, while it was detected in only one case with other forms of GN. The deposited MBL/MASP-1 was observed to associate with C3b/C3c and C5b-9 but not with IgG, IgM, C1q, C4c, or properdin. Compared with MBL/MASP-1 negative cases with IgA-N, the positive cases with IgA-N were young and the renal biopsies had been performed at an early stage of the disease. No significant correlation was found between glomerular deposition of MBL/MASP-1 and proteinuria, haematuria, creatinine clearance, and serum levels of IgA, C3, or C4 at the time of renal biopsy. There were also no significant differences between MBL/MASP-1 positive cases and negative cases in the plasma levels of circulating immune complexes or soluble C5b-9. CONCLUSION: The lectin pathway of complement activation, which is initiated by the MBL/MASPs complex, evidently contributes to the development of glomerular injury in a significant number of cases with IgA-N. In addition, these findings will add insight to the pathogenesis of IgA-N, including its relation to infection, since MBL plays a crucial role in the host defense against various pathogens.
Adolescent↗
The association of physical activity level characteristics and other lifestyles with obesity in Nagoya University alumni, Japan.
Improving daily-life habits is considered to be effective in treating obesity. We have examined obesity in regular physical examinations in university students since 1974. In this study, the subjects were 199 students regarded as obese (Broca's index: more than 120%) and 326 non-obese students randomly selected (525 subjects in total) among students who underwent regular physical examinations at Nagoya University, Japan, between 1974 and 1978. Here we report our follow-up survey of obese university students and non-obese individuals who were students of the same university during the same period. This study was carried out for the purpose of clarifying the relationship between changes in lifestyle and body weight 20 years after graduation. Concerning eating behavior, a higher proportion of subjects cared about diet intake in the current non-obese group than in the current obese group (P<0.05). The meal-time in the obese was shorter than that in the non-obese group (P<0.01). Ten percent of subjects in the obese group and 24.4% of subjects in the non-obese group selected class II (moderate) or higher as indicative of the intensity of their daily physical activity. There was a significant difference in distribution between the groups (P<0.05). In the group showing improvement in obesity over time, a higher proportion of subjects cared about diet intake than in the group with continued obesity (P<0.05). Concerning intensity of physical activity, 11.8% of subjects in the group with continued obesity selected class II (moderate) or higher, while 45.5% of subjects in the group showing improvement in obesity chose class II (moderate) or higher. A significant difference in distribution existed between the groups (P<0.01). These findings suggest that the eating behavior of ending meals before feeling satiety and a lifestyle change to enhance the intensity of daily physical activity including walking, even if not having any special sports habits, are effective in decreasing body weight.
Adult↗
Appearance of nephrotic syndrome following interferon-alpha therapy in a patient with hepatitis B virus and hepatitis C virus coinfection.
A 59-year-old woman with hepatitis B surface antigen (HBsAg) and hepatitis C viral (HCV) antibody presented with proteinuria and hematuria. The patient was treated with interferon-alpha (INF-alpha) because plasma aminotransferase levels had been elevated and a liver biopsy had showed chronic active hepatitis. Her urinary protein excretion decreased as liver function normalized and her serum HCV-RNA was negative during treatment. Eleven weeks after completion of INF-alpha treatment, she suddenly presented with nephrotic-range proteinuria, although an improvement in the hepatic function was maintained. Renal pathologic findings were consistent with membranous glomerulonephritis (MGN), and HBsAg was detected in the glomeruli but not HCV. After treatment with prednisolone, her 24-hour protein excretion was below 0.7 g/day. To our knowledge this is the first report on hepatitis B virus MGN with nephrotic syndrome following IFN-alpha therapy for HCV. This suggests that treatment with INF-alpha might affect the immune processes and may be associated with the pathogenic mechanism in this patient.
Anti-Inflammatory Agents↗
Intramuscular 3-hydroxybutyrate levels after 60 tetani/min contraction in diabetic and non-diabetic rats.
Post-exercise hyperketonemia in poorly-controlled diabetic patients is a well recognized phenomenon, but because studies concerning changes in ketone body metabolism in muscle during and/or after exercise are scarce, we measured the intramuscular 3-hydroxybutyrate (3-OHBA) and lactate concentrations in 12 diabetic (streptozotocin-induced; 60 mg/kg, ip) and 13 non-diabetic control rats before and after a 1-h muscle contraction. One thigh tetanic contraction was elicited at a tetanic frequency of 60 tetani/min and the other thigh was kept resting. We used a microdialysis technique in both quadriceps muscles, vastus lateralis, and the right jugular vein. Blood flow in both femoral muscles was also monitored before and after contraction. Dialysate 3-OHBA and lactate levels in contracting and non-contracting muscles and in blood showed a significant increase after contraction (P<0.05) in diabetic rats. In control rats there was no significant change in dialysate 3-OHBA or the lactate concentration in contracting and non-contracting muscles or in blood before and after contraction. A significant increase in contracting muscle blood flow was observed only for the first 5 min after contraction in diabetic and control rats. These results suggest that 3-OHBA uptake in contracting muscle is reduced, and that this phenomenon may play a role in post-exercise ketosis in diabetes.
3-Hydroxybutyric Acid↗
[Beneficial effect of salazosulfapyridine (SASP) in a patient with secondary renal amyloidosis].
A 55-year old female with rheumatoid arthritis (RA) had presented with proteinuria since July 1996. She was referred to us for persistent edema on her face and legs in November 1996. On admission, her 24-hour urinary protein excretion was 4.4 g/day, total serum protein level was 5.3 g/dl, and serum level of amyloid A protein (SAA) was elevated to 45.8 mg/ml. A percutaneous renal biopsy was performed, and light microscopy revealed varying degrees of amyloid deposits in the mesangial areas and arteriolar walls. The diagnosis of secondary amyloidosis (AA amyloidosis) was based on immunohistochemical staining for amyloid A protein using monoclonal antibody against SAA. Four weeks after treatment with salazosulfapyridine (SASP) and dipyridamole, proteinuria began to decrease and the edema had disappeared. Finally she recovered from nephrotic syndrome. AA amyloidosis has been thought to have a poor prognosis, with progression to renal failure. Since there is no specific effective therapy for the disease, it is very important to reduce the activity of the underlying cause. In our patient with renal amyloidosis following RA, SASP was evidently effective for arthritis and improvement of renal function. SASP might have a beneficial effect on AA amyloidosis by suppressing inflammatory cytokines.
Amyloidosis↗
Level of red blood cells in the urinary sediment reflects the degree of renal activity in Wegener's granulomatosis.
Symptoms due to renal lesions often disappear and smolder by successful treatment during the first episode of Wegener's granulomatosis (WG). It is indispensable to recognize an increase in disease activity and provide adequate treatment to inhibit the progression of renal dysfunction as well as regulate disease activity in patients with WG. We gave attention to red blood cells in urinary sediment (U-RBC), a criterion in the diagnosis of WG, to more exactly determine the degree of renal activity. Comparison of level of U-RBC with other laboratory data and renal histology was performed in the clinical course of six cases. The level of U-RBC altered reversibly during the period studied and correlated with the C-reactive protein level and erythrocyte sedimentation rate which reflect disease activity in cases with microhematuria before treatment. When U-RBC disappeared within eight weeks after treatment, glomerular histological change remained small. The reported cases revealed that the alteration in U-RBC was more sensitive and more specific for renal involvement than the other disease markers. In conclusion, the level of U-RBC reflects the degree of renal activity in WG. We propose that the quantitation of U-RBC is extremely useful in following patients with WG.
Adult↗