Complement activation contributes to both glomerular and tubulointerstitial damage in adriamycin nephropathy in mice.
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Adriamycin nephropathy is a model of focal segmental glomerulosclerosis, characterized by proteinuria and progressive glomerulosclerosis and tubulointerstitial damage. In this study, we examined the role of complement in the etiology of adriamycin nephropathy in mice. We used mice deficient in C1q, factor D, C3, and CD59, and compared them with strain-matched controls. C3 deposition occurred in the glomeruli of wild-type mice as early as 48 h following a single i.v. injection of adriamycin. C3-deficient mice developed significantly less proteinuria and less podocyte injury at day 3 postadriamycin than controls, suggesting that complement is important in mediating the early podocyte injury. At later time points, C3-deficient mice were protected from glomerulosclerosis, tubulointerstitial injury, and renal dysfunction. Factor D-deficient mice were also protected from renal disease, confirming the importance of alternative pathway activation in this model. In contrast, C1q-deficient mice developed similar disease to controls, indicating that the complement cascade was not activated via the classical pathway. CD59-deficient mice, which lack adequate control of C5b-9 formation, developed significantly worse histological and functional markers of renal disease than controls. Interestingly, although more C9 deposited in glomeruli of CD59-deficient mice than controls, in neither group was tubulointerstitial C9 staining apparent. We have demonstrated for the first time that alternative pathway activation of complement plays an important role in mediating the initial glomerular damage in this in vivo model of focal segmental glomerulosclerosis. Lack of CD59, which regulates the membrane attack complex, led to greater glomerular and tubulointerstitial injury. (+info)
Complement factor D, albumin, and immunoglobulin G anti-band 3 protein antibodies mimic serum in promoting rosetting of malaria-infected red blood cells.
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Rosetting of Plasmodium falciparum-infected red blood cells (parasitized RBC [pRBC]) with uninfected RBC has been associated in many studies with malaria morbidity and is one form of cytoadherence observed with malarial parasites. Rosetting is serum dependent for many isolates of P. falciparum, including the strains FCR3S1.2 and Malayan Camp studied here. We identified the three naturally occurring components of sera which confer rosetting. Complement factor D alone induced 30 to 40% of de novo rosetting. Its effect was additive to that of 0.5 mg/ml albumin and to that of 15 ng/ml of naturally occurring antibodies to the anion transport protein, band 3. The three components together mediated rosetting as effectively as 10% serum. De novo rosetting experiments showed that naturally occurring anti-band 3 antibodies as well as factor D were effective only when added to pRBC. Factor D appeared to cleave a small fraction of a protein expressed on the surface of pRBC. (+info)
The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood.
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The relative role of complement and CD14 in Escherichia coli-induced leukocyte CD11b up-regulation, phagocytosis, and oxidative burst in human whole blood was examined. The highly specific thrombin inhibitor lepirudin was used as anticoagulant, as it does not affect complement activation. Complement inhibition at the level of C3 (anti-C2 and anti-factor D) and C5 (C5a receptor antagonist and anti-C5/C5a) efficiently inhibited CD11b up-regulation, phagocytosis, and oxidative burst in granulocytes. Monocyte activation was generally less complement-dependent, but when C3 activation was blocked, a pronounced inhibition of phagocytosis and oxidative burst was obtained. Only the combination of anti-C2 and antifactor D blocked E. coli C3 opsonization completely. Whole E. coli, disrupted E. coli, and the C3-convertase activator cobra venom factor up-regulated CD11b rapidly on both cell types, proportional to their complement activation potential in the fluid phase. In comparison, purified LPS at concentrations comparable with that present in the E. coli preparations did not activate complement. Oxidative burst was induced only by whole bacteria. Finally, the combination of complement inhibition and anti-CD14 completely blocked E. coli-induced granulocyte and monocyte CD11b up-regulation and quantitatively, virtually abolished phagocytosis. The results indicate that complement and CD14, despite differential effects on granulocytes and monocytes, are the two crucial, quantitative factors responsible for E. coli-induced CD11b, phagocytosis, and oxidative burst in both cell types. (+info)
Regulation of adipose cell differentiation. I. Fatty acids are inducers of the aP2 gene expression.
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The regulation of the expression of adipose-related genes, i.e., aP2, adipsin, and glycerophosphate dehydrogenase (GPDH) by growth hormone (GH) and polyamines, as well as the role of fatty acids, have been investigated in polyamine-dependent Ob1754 cells and Ob1771 preadipose cells. Growth hormone acts as an obligatory hormone for adipsin and GPDH gene expression but its presence is not required for the expression of the aP2 gene. In fully differentiated Ob1771 cells, impairment of fatty acid synthesis by glucose deprivation leads to an inhibition of the aP2 gene expression, whereas the expression of adipsin and GPDH genes remains unaffected. Supplementation of the culture medium with fatty acids prevents the decrease of aP2 gene expression, and this effect appears primarily due to an increase in the transcriptional level of aP2 gene. The induction of aP2 gene has been examined in early committed, lipid-free Ob1771 cells in which fatty acid synthesis is very low despite glucose supplementation. Long-chain fatty acids (greater than or equal to C12) are able to activate the aP2 gene. It is concluded that fatty acids or fatty acid metabolites activate the aP2 gene and subsequently modulate its expression. (+info)
Eliminating complement factor D reduces photoreceptor susceptibility to light-induced damage.
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PURPOSE: Genetic risk factors such as variations in complement factors H (CFH) and B (CFB) have been implicated in the etiology of age-related macular degeneration. It has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis. The authors tested the involvement of the complement system in an experimental model for oxidative stress-mediated photoreceptor degeneration, the light-damage mouse model. METHODS: Changes in gene expression were assessed in BALB/c retinas in response to constant-light (CL) exposure using microarrays and real-time PCR. Susceptibility to CL exposure was tested in CFD(-/-) mice on a BALB/c background. Eyes were analyzed using electrophysiologic and histologic techniques. RESULTS: Genes encoding for proteins involved in complement activation were significantly upregulated after CL. The altered gene profiles were similar to proteins accumulated in drusen and to genes identified in the retina and RPE/choroid of patients with age-related macular degeneration. Cyclic-light reared CFD(-/-) and CFD(+/+) mice had indistinguishable rod function and number; however, after CL challenge, CFD(-/-) photoreceptors were significantly protected. CONCLUSIONS: These results suggest that rod degeneration in the CL-damaged retina involves the activity of the alternative complement pathway and that eliminating the alternative pathway is neuroprotective. Thus, the light damage albino mouse model may be a good model to study complement-mediated photoreceptor degeneration. (+info)
Acylation-stimulating protein deficiency and altered adipose tissue in alternative complement pathway knockout mice.
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Acylation-stimulating protein (C3adesArg/ASP) is an adipokine that acts on its receptor C5L2 to stimulate triglyceride (TG) synthesis in adipose tissue. The present study investigated ASP levels in mouse models of obesity and leanness and the effect of ASP deficiency in C3 knockout (C3KO) mice on adipose tissue morphology. Plasma ASP levels in wild-type (WT) mice correlated positively with plasma nonesterified fatty acids (NEFA) (R = 0.664, P < 0.001) and total cholesterol (R = 0.515, P < 0.001). Plasma ASP was increased by 85% in obese ob/ob leptin-deficient mice and decreased in lean diacylglycerol acyltransferase 1 (DGAT1) KO mice (-54%) and C/EBPalpha(beta/beta) transgenic mice (-70%) compared with WT. Mice lacking alternative complement factor B or adipsin (FBKO or ADKO), required for ASP production, were also ASP deficient. Both FBKO and C3KO mice had delayed postprandial TG and NEFA clearance on low-fat (LF) and high-fat (HF) diets, suggesting that lack of ASP, not C3, drives the metabolic phenotype. Adipocyte size distribution in C3KO mice was polarized (increased number of both small and large cells), with decreased adipsin expression (-33% gonadal HF), DGAT1 expression (-31% to -50%) and DGAT activity (-41%). Overall, a reduction/deficiency in ASP is associated with an antiadipogenic state and ASP may provide a target for controlling fat storage. (+info)
Reduced white fat mass in adult mice bearing a truncated Patched 1.
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Hedgehog (Hh) signaling emerges as a potential pathway contributing to fat formation during postnatal development. In this report, we found that Patched 1 (Ptc1), a negative regulator of Hh signaling, was expressed in the epididymal fat pad of adult mice. Reduced total white fat mass and epididymal adipocyte cell size were observed in naturally occurring spontaneous mesenchymal dysplasia (mes) adult mice (Ptc1(mes/mes)), which carry a deletion of Ptc1 at the carboxyl-terminal cytoplasmic region. Increased expression of truncated Ptc1, Ptc2 and Gli1, the indicators of ectopic activation of Hh signaling, was observed in epididymal fat pads of adult Ptc1(mes/mes) mice. In contrast, expression of peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, adipocyte P2 and adipsin were reduced in epididymal fat pads of adult Ptc1(mes/mes) mice. Taken together, our results indicate that deletion of carboxyl-terminal tail of Ptc1 can lead to the reduction of white fat mass during postnatal development. (+info)
Initiation of the alternative pathway of murine complement by immune complexes is dependent on N-glycans in IgG antibodies.
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