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PubMed1976

C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase.

C3 nephritic factor (C3NeF) defined by the capacity of nephritic serum and its fractions to initiate loss of the B antigen of C3 in normal serum was purified from the serum of three different donors and shown to function by stabilization of membrane-bound and fluid phase alternative pathway C3 convertase. C3NeF converts cell-bound C3B sites in a dose-related manner to CEB(NeF) sites, which exhibit an approximate 10-fold increase in half-life. The linear relationship between the C3NeF input and the residual hemolytic sites on EAC43B present after incubation for 20 min at 30 degrees C, during which labile C3B sites have decayed, indicates that the number of residual C3B sites is directly related to the dose of C3NeF. The capacity of C3NeF to stabilize the C3B convertase in a temperature- and dose-dependent manner, which is independent of binding or consumption of C3NeF, in a fluid phase reaction mixture of 125I-B, 131I-C3 and D permits isolation of a 10S complex containing radiolabeled C3 and B and exhibiting C3, convertase activity on an exogenous C3 source. Thus, the stabilizing effect of C3NeF is not limited to membrane-bound C3B but is also sufficient to permit recovery of a fluid phase C3 convertase formed during the interaction of C3, B, and D.

Binding Sites↗
PubMedDate not supplied

Inducible nitric oxide synthase induction in Thy 1 glomerulonephritis is complement and reactive oxygen species dependent.

Thy 1 glomerulonephritis (GN) is a rat model of complement-dependent immune mesangial injury with induced glomerular nitric oxide (NO) synthesis. To examine mechanisms of inducible nitric oxide synthase (iNOS) induction, we studied the effects of treatment with the antioxidant N-acetyl-cysteine (NAC) and soluble complement receptor 1 (sCR1). Thy 1 GN was induced by intravenous anti-Thy 1 antibody. Glomeruli were isolated and kidney tissue taken from 30 min to 24 h after induction. Nitrite (NO-2) synthesis, luminol chemiluminescence for reactive oxygen species (ROS), and iNOS and cytokine mRNA were assayed in isolated glomeruli. Mesangial injury (mesangiolysis) and leucocyte infiltration were quantitated on tissue sections. NAC (i.p. 1,000 mg/kg, 1 h prior to anti-Thy 1) reduced glomerular NO-2 synthesis (3.5 +/- 0.66 vs. untreated 8.2 +/- 1.1, p = 0.02), and iNOS mRNA expression, and abolished enhanced chemiluminescence. In vitro incubation of nephritic glomeruli with 20 mM NAC also suppressed nitrite production (4.7 +/- 0.8 vs. untreated 12.2 +/- 0. 7 nmol NO-2/2,000 glomeruli/48 h, p = 0.003), and chemiluminescence. In NAC-treated animals, neutrophil infiltration (0.5 +/- 0 vs. untreated 9.6 +/- 1.6 glomerulus, p = 0.0005), and macrophage infiltration (1.7 +/- 0.4 vs. untreated 12.0 +/- 0.1, p = 0.006) were abolished, and mesangiolysis was significantly reduced (45.9 +/- 1.3 vs. untreated 34.4 +/- 2.1 cells/glomerulus, p = 0.009). NAC did not inhibit anti-Thy 1 antibody deposition. C1q was unaffected, but C3 was reduced. sCR1 treatment prevented iNOS mRNA induction, the enhanced chemiluminescence, and the neutrophil infiltration at 1 h. IL-1beta and TNFalpha mRNAs were not affected by either NAC or sCR1. These results show that NAC inhibits iNOS induction and NO synthesis in this model, and suppresses ROS synthesis and injury. They suggest that complement-dependent ROS generation is the critical initiating event that follows fixation of anti-Thy 1 antibody.

Acetylcysteine↗
PubMed1984

Reduction of phagocyte adherence by nephritic sera: relation to complement activation.

Phagocytes isolated from either normal donors or from patients with poststreptococcal (P-SGN), lupus erythematosus (SLE-GN), or membranoproliferative (MPGN) glomerulonephritis showed normal adherence to glass (PAg) after incubation in normal human serum (NHS), but was reduced after incubation in patient serum. Low PAg was the consequence of incubation of normal phagocytes with the earliest available sera from all 22 P-SGN patients, 28 of 37 SLE-GN patients, 19 of 25 patients with MPGN type I, all 10 with types II and III, and all 5 with nephritis associated with chronic bacteremia. Low C3 and decreased PAg were related by regression analysis in sera from patients with P-SGN (P less than 0.001), SLE-GN (P less than 0.005), and MPGN (P less than 0.001) type I. In patients with P-SGN and one patient with nephritis associated with chronic bacteremia, complement levels and PAg returned to normal in parallel with clinical improvement. In vitro, PAg was reduced by NHS treated with either zymosan or bovine serum albumin (BSA)-anti-BSA complexes but neither BSA-anti-BSA complexes or zymosan, previously incubated in NHS, reduced PAg. PAg was normal in serum deficient in C4 or C5 unless treated with zymosan.

Adult↗
PubMedDate not supplied

Proinflammatory effects in experimental mesangial proliferative glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin derivative.

BACKGROUND/AIM: The new immunosuppressant SDZ RAD, a rapamycin derivative, inhibits growth factor driven cell proliferation. SDZ RAD designed for transplantation may also be a candidate agent to treat inflammatory kidney diseases. Therefore, we investigated the effects of SDZ RAD in two different animal models of glomerulonephritis, in anti- Thy1.1 nephritis and in acute puromycin aminonucleoside (PAN) nephrosis. METHODS: Eighty-seven male Wistar rats were investigated. Anti-Thy1.1 nephritis: healthy rats (n = 9), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 9), SDZ RAD placebo treated nephritic rats (n = 6), SDZ RAD-pretreated nephritic rats (n = 9), and early (n = 6) as well as delayed (n = 6) SDZ RAD-posttreated nephritic rats. PAN nephrosis: healthy rats (n = 6), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 12), and SDZ RAD-pretreated nephritic rats (n = 12). In a separate study, 12 male Sprague-Dawley rats were analyzed in anti-Thy1.1 nephritis: healthy rats (n = 3), nephritic rats (n = 3) and pretreated nephritic rats (n = 6). SDZ RAD and SDZ RAD placebo were given at single doses of 2.5 mg/kg body weight per day by gavage. The experiments lasted until days +2 and +9 after induction of anti-Thy1. 1 nephritis and until day +13 in the case of PAN nephrosis. RESULTS: In anti-Thy1.1 nephritis, SDZ RAD demonstrated marked proinflammatory effects in a time-dependent manner, as reflected by severe focal damage to glomerular histology including inhibition of mesangial cell proliferation, reduction of creatinine clearance, and increase in plasma creatinine levels as well as proteinuria. Almost identical results were obtained in both rat strains. In contrary, SDZ RAD ameliorated significantly the development of PAN nephrosis. Animals pretreated by this agent showed a significant reduction of proteinuria and of glomerular invasion of monocytes/macrophages. CONCLUSION: Some caution is warranted for the use of SDZ RAD in inflammatory glomerular diseases, since it accentuated glomerular damage induced by anti-Thy1.1 antibodies.

Animals↗
PubMed1999

Effect of renovascular hypertension on experimental glomerulonephritis in rats.

Systemic hypertension is a major risk factor that determines the rate of progression of kidney disease. The underlying mechanisms, however, are incompletely understood. To gain insight into these mechanisms, the present study was undertaken to characterize the effects of renovascular hypertension on the course of anti-thymocyte antibody-induced glomerulonephritis. Glomerulonephritis was induced in rats 6 weeks after the initiation of two-kidney, one-clip hypertension, when blood pressure was already increased. Structure and function of the clipped and the nonclipped kidney were examined 5 days later. Glomerular filtration rate (GFR) was measured by inulin clearance. The induction of nephritis did not alter the blood pressure in either hypertensive rats or normotensive controls. Albuminuria increased slightly in normotensive rats after the induction of nephritis, whereas no significant differences were found between hypertensive rats with or without nephritis. No significant differences were found for the GFR values of normotensive controls and nephritic animals or for values in the clipped kidney with or without nephritis. However, the GFR of the nonclipped kidney was significantly reduced in nephritic animals as compared with all other groups. Morphologic evaluation revealed that hypertensive rats with nephritis exhibited a combination of characteristics of nephritis and hypertensive glomerular injury. Histologic findings of nephritis, such as glomerular binding of rabbit IgG and glomerular proliferation and mesangial matrix expansion, were similar after the induction of nephritis in controls and in the clipped and nonclipped kidneys of hypertensive animals. However, intraglomerular microaneurysms were significantly more often found in the non-clipped kidneys after the induction of nephritis. Hypertension-induced deterioration of glomerular function was not associated with marked morphologic deterioration but rather with a combination of the characteristics of nephritis and hypertensive glomerular injury.

Albuminuria↗
PubMed1996

Decrease of glomerular disialogangliosides in puromycin nephrosis of the rat.

Puromycin aminonucleoside nephrosis (PAN) is a model for human minimal change nephropathy induced in rats by injection of puromycin. In PAN, defective sialylation of a major sialoprotein of podocytes, podocalyxin, has been demonstrated and the consequent decrease of anionic charge suggested as a causative factor for increased glomerular permeability and proteinuria. Whether defective sialylation is a general feature of PAN affecting also glomerular glycosphingolipids is not known. We have shown that rat glomeruli are rich in disialogangliosides GD3 and O-acetyl GD3, the functions of which are not known. Here, we made a sequential analysis of the glomerular gangliosides, especially of GD3 and its O-acetyl derivative in acute PAN using immunohistochemical and biochemical techniques and compared the results with another rat model of glomerular disease, Heymann nephritis. The prominent immunohistochemical finding was the almost total disappearance of glomerular O-acetyl GD3 and a substantial decrease of its precursor GD3 peaking at 10 days after injection of puromycin. Segmental areas lacking these gangliosides remained in glomeruli still at 30 days after injection. The response was dose dependent. Semiquantitative analysis by thin layer chromatograms showed that O-acetyl GD3 was decreased by 41% already at 3 days and by 60% at 10 days after injection of puromycin. Also GD3, the immediate precursor of O-acetyl GD3, was decreased by 20 and 19%, respectively, at 3 and 10 days after injection. At 3 days after injection, overt proteinuria had not started. At these times, no other changes were observed in the glomerular gangliosides. The decrease of glomerular GD3 and O-acetyl GD3 indicates a decrease of GD3 synthase activity and perhaps of O-acetyltransferase activity in PAN nephrosis. As these changes preceded the overt proteinuria, they may have a causal relationship to it. In the glomeruli of Heymann nephritic rats, no similar changes were seen, suggesting that the sialylation defect is not due to proteinuria but is a consequence of targeted puromycin action on cells.

Albuminuria↗