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*
Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan; and
Center for Experimental Therapeutics and Departmentof Pharmacology, and
Renal-Electrolyte and Hypertension Division, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The identification and study of human DAF have historically been associated with the human hematological disorder paroxysmal nocturnal hemoglobinuria (PNH) (12, 13, 14). PNH is caused by a combined deficiency of DAF and CD59 on the affected blood cells of the patients (12). As a result of DAF and CD59 deficiency, blood cells of PNH patients are not protected from autologous complement attack. In addition to circulating blood cells, DAF is also expressed prominently on many other cell types such as endothelial and epithelial cells (5, 15). For example, in the human kidney DAF has been detected in the glomerulus on mesangial and epithelial cells (16, 17).
In principle, DAF should also protect these cells from complement-mediated inflammatory damage. This may be particularly true in an autoimmune disease setting in which either binding of autoantibodies to specific tissue Ags or formation of immune deposits in vital organs, such as the kidney, activates the classical complement pathway. Although in vitro studies have demonstrated that DAF expressed on these cells is functional as a C3 convertase inhibitor (17, 18), thus far little direct evidence is available to corroborate the expectation that DAF plays a protective role in vivo on nonvascular cells from complement-mediated injury. In humans, rare cases of complete DAF deficiency due to germline mutation of the DAF gene (Inab serological phenotype) have been identified (19, 20). These individuals differ from PNH patients in that they lack DAF expression in all their tissues, whereas DAF deficiency in PNH patients, resulting from somatic mutations of a gene critical to GPI-anchor biosynthesis (21), is limited to affected blood cells and occurs in conjunction with CD59 dysfunction (12). Furthermore, although DAF gene mutation apparently did not lead to PNH-like disease, two of the five individuals had an intestinal inflammatory disorder (19, 20). However, due to the rare nature of DAF gene mutation in the human population, it has not been possible to determine whether such individuals are more susceptible to complement-mediated inflammatory tissue damage.
To address this issue and to aid the study of DAF biology in vivo, we cloned the mouse homologue of human DAF (22) and generated a knockout mouse that completely lacks the expression of the GPI-DAF gene product (23). In the mouse, two DAF genes, arranged in tandem on mouse chromosome 1, have been identified (22, 24, 25). One DAF gene, termed GPI-DAF, is equivalent to human DAF in that it encodes a GPI-anchored protein and is expressed broadly in mouse tissues (22, 24, 25). The second DAF gene, termed TM-DAF, encodes a transmembrane DAF and is expressed only on mouse sperm (22, 24, 26). Additionally, the mouse and the rat express in many of their tissues a rodent-specific transmembrane C3 regulator called Crry (7, 8, 9). Crry was established to possess both DAF and MCP activities (7, 8, 9) and may play the substituting role for MCP in most mouse and rat tissues because the MCP gene is expressed only in the testes in these two species (27, 28). The fact that GPI-DAF knockout mice could survive and function normally (23) also suggests that Crry may be able to compensate DAF function in regulating spontaneous (alternative pathway) complement activation. However, the relative role of DAF and Crry as membrane regulators in preventing classical pathway complement activation in vivo is not clear.
In this study, we used the GPI-DAF knockout mice and investigated their susceptibility to complement-mediated inflammatory damage in a well-established autoimmune disease model, anti-glomerular basement membrane (GBM) Ab induced glomerulonephritis in mice (29, 30). The involvement of the complement system in anti-GBM glomerulonephritis has been well documented (31, 32). For example, mice deficient in the complement components C3 and C4 were partially protected from anti-GBM glomerular injury (33), and depletion of complement by cobra venom factor in rats and rabbits reduced the degree of inflammation and disease progression (34, 35). Furthermore, a soluble form ofrecombinant Crry, either administered as a fusion protein orproduced in vivo through transgenic expression, has been demonstrated to attenuate the development of Ab-induced glomerulonephritis in the mouse (36, 37, 38). Nevertheless, there are complement-dependent and independent inflammatory responses initiated by nephrotoxic Abs that may in part be related to the Ab dosage (33, 34). We demonstrate in this study that a calibrated dose of anti-GBM serum caused severe glomerulonephritis in GPI-DAF knockout mice but not in wild-type controls. This result offers direct evidence that DAF protects self-tissues from complement attack in an autoimmune disease setting and suggests that activity of membrane C3-regulatory proteins is a critical determinant for complement susceptibility in autoimmune tissue injury.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GPI-DAF-deficient mice were generated as described previously (23). In brief, the first three exons of the GPI-DAF gene were deleted and replaced with the NEO gene. As expected, no GPI-DAF was expressed in the knockout mouse tissues because the proximal promoter sequence necessary for RNA transcription and the first two short consensus repeats (encoded by exons 2 and 3, respectively) were absent. This was confirmed by Northern blotting analysis (23). In contrast to the total abrogation of GPI-DAF gene expression, TM-DAF gene expression in the knockout mouse testis was unaffected (23). These GPI-DAF-null mice could develop, grow, and reproduce normally (23). The original C57BL/6–129J knockout mice were backcrossed with C57BL/6 mice for four generations. Because the founder knockout mice had >50% C57BL/6 background (C57BL/6 blastocyst were used in the generation of chimera, and C57BL/6 females were used in the subsequent germline transmission breeding), the four times-backcrossed mice should have a predominantly C57BL/6 background (>97%). Littermates of the backcrossed mice were intercrossed to obtain wild-type and DAF knockout founder mice. Age- and sex-matched F1 mice were used in all experiments. Mice were housed in a specific pathogen-free facility and were confirmed to be negative for common murine viral pathogens by sera analysis. Experiments were conducted by following established guidelines for animal care and all protocols were approved by the appropriate institutional committees.
Preparation of rabbit anti-GBM serum
The anti-mouse GBM serum was prepared as described by Nagai et al. (30). Briefly, glomeruli were isolated by differential sieving from the renal cortex and were disrupted by sonication. The GBM fraction was collected by centrifugation at 76,000 x g for 60 min. Anti-GBM serum was raised in Japanese white rabbits by repeated (five times) immunization with purified mouse GBM. For the immunization step, 1 mg GBM protein was emulsified with 1 ml CFA (Difco Laboratories, Detroit, MI) and was administered to the rabbit by s.c. injection.
Induction of anti-GBM nephritis
Anti-GBM nephritis was induced according to a previously described protocol by Nagai et al. (30). Mice were immunized i.p. with 0.5 mg rabbit IgG per 20 g body weight emulsified with CFA. Five days after immunization, 0.05 ml anti-GBM serum per 20 g body weight, diluted with 5 parts of saline, was administered intravenously through the orbital plexus. In preliminary experiments, a dose-response curve was established to determine a dose that did not produce nephritis (see below) in normal mice despite glomerular deposition of IgG.
Experimental design
Mice between 6 and 8 wk of age were used in this study. Preliminary experiments indicated that male knockout mice were more sensitive than the females to disease induction, presumably reflecting the higher level of complement activity in male mice in general (39, 40). Accordingly, only male mice were used in experiments. Mice were sacrificed either at 8 h (knockout, n = 5; wild-type, n = 10) or on day 8 (knockout, n = 8, wild-type, n = 5) after administration of a subnephritogenic dose of anti-GBM serum. The kidneys were processed and evaluated as described below. Serum and urine samples were collected at day 8. For urine collection, the mice were housed in individual metabolic cages with free access to tap water.
Northern blot and RT-PCR analyses
Total tissue RNAs were extracted with Trizol reagent (Life Technologies, Gaithersburg, MD), fractionated in a 1% agarose gel, and transferred to Hybond-N+ nylon membranes. To detect GPI-DAF mRNAs, a 276-bp 3'-cDNA-specific fragment (22) was used as a probe for hybridization in QuickHyb solution (Stratagene, La Jolla, CA). To detect TM-DAF mRNA, the membrane was stripped and rehybridized with a 180-bp specific probe corresponding to the 3'-cDNA of TM-DAF (22). Finally, the membrane was stripped again and hybridized with a control probe (GAPDH) to confirm equal loading of RNAs. First strand cDNAs for RT-PCR were synthesized as previously described (22) using total RNAs from kidneys and oligo(dT) as a primer. The following two primers were used to amplify mouse GPI-DAF cDNA: 5'-CATACATGTTTAATAACCTTGACAGTTTTG-3' (upstream) and 5'-AACAAACAACACTATTAAATTTATTGTATCC-3' (downstream). The following two primers were used to amplify mouse Crry cDNA: 5'-CCAGCCCCATCACAGCTTCCTTCT-3' (upstream); and 5'-CTTCCCTCTCGCATCAGTGTT-3' (downstream).
Western blot analysis
Membrane proteins of kidneys were solubilized as previously described (41). In brief, kidneys were washed with PBS twice; homogenized in a 20x volume of PBS, pH 7.2, containing 10 mM EDTA, 1% Nonidet P-40, 0.1 mM PMSF, 1 µg/ml leupeptin, and 1 µg/ml pepstatin A with a Polytron (Polytron, Paterson, NJ); and then solubilized for 30 min at 4°C. Nuclei and cytoplasmic debris was then pelleted at 14,000 rpm using a microcentrifuge for 10 min at 4°C.
SDS-PAGE was performed with 300 µg/lane of solubilized kidney samples under nonreducing condition. Western blot to detect Crry expression was performed using 1F2 (10 µg/ml; PharMingen, San Diego, CA), a rat anti-mouse Crry mAb (8). The bound Ab was then detected with alkaline phosphatase-conjugated goat anti-rat IgG, (1/500; Promega, WI). 5-Bromo-4-chloro-3-indolyl phosphate/NBT (Sigma, St. Louis, MO) was used as a substrate for alkaline phosphatase.
Histology
Renal cortical tissue for light microscopy was fixed in methyl Carnoy’s solution and embedded in paraffin. Sections of 4 µm were cut and stained with periodic acid-Schiff and counterstained with hematoxylin. To accurately perform quantitative analysis, computer-assisted morphometry was used (42). For each individual animal, nine photographs of randomly chosen areas of a cortex were taken at x200 magnification. Each photograph included one to four glomeruli, and its genotype was blinded to eliminate potential experimental bias. The photographs were converted to picture files using a scanner at a resolution of 300 dots per inch and were evaluated on a video screen using Photoshop software (Adobe Systems, San Diego, CA). Only equatorially sectioned glomeruli were evaluated. With this method, total glomerular nuclear counts, percentage of glomeruli exhibiting glomerular injury, and glomerular tuft volume were determined. Glomerular injury was defined by evidence of segmental increases in glomerular matrix, segmental collapse and obliteration of capillary lumina and accumulation of hyaline which was frequently associated with synechial attachments to Bowman’s capsule. To measure the glomerular tuft volume, mean planar glomerular area was first determined and was used to calculate glomerular tuft volume by a previously described formula (43). The mean planar glomerular area was determined by manually tracing the outer edges of all glomerular tufts in each kidney section and then calculating and summarizing the encircled areas by computerized morphometry (44).
Immunofluorescence
To examine the deposition of C3, 4-µm frozen sections were stained with FITC-conjugated goat Abs against mouse C3 (1/100; Cappel, ICN Pharmaceuticals, Aurora, OH). For fibrinogen, FITC-conjugated goat Abs against rat fibrinogen, which have cross-reactivity with the mouse fibrinogen (1/400; Cappel, ICN Pharmaceuticals) was used. For semiquantitative analysis of rabbit IgG deposition in glomeruli, indirect immunofluorescence using biotinylated goat anti-rabbit IgG (1/400; Vector Laboratories, Burlingame, CA) and NeutrAvidin-Oregon Green 488 conjugate (Molecular Probes, Eugene, OR) was used. Fluorescence-positive glomeruli were counted, and the percentage of positive glomeruli in each sample was calculated. Deposition of autologous (mouse) IgG in the glomeruli was assessed by using biotinylated goat anti-mouse IgG (1/400; Vector) andNeutrAvidin-Oregon Green 488 conjugate.
Measurement of circulating IgG and IgM levels
Circulating levels of total IgG and IgM were determined with the Mouse IgG ELISA kit and Mouse IgM ELISA kit (Bethyl Laboratories, Montgomery, TX) according to the manufacturer’s protocol. Circulating levels of rabbit IgG-specific mouse IgG were measured by ELISA using the procedure detailed below. Ninety-six-well ELISA plates coated with rabbit IgG (Organon Teknika, Durham, NC) were incubated with test plasma that was diluted to 1/2000. After being washed extensively with PBS containing 0.05% Tween 20, the plates were incubated with HRP-conjugated anti-mouse IgG (Vector) diluted to 1/1000. For the development, the wells were incubated with the reaction solution containing 3,3',5,5'-tetramethylbenzidine (Sigma). The reaction was stopped by addition of H2SO4, and the OD450 was determined and taken as a measurement of anti-rabbit IgG Abs.
Measurement of urinary albumin and blood urea nitrogen (BUN)
Urinary albumin excretion was measured by a mouse albumin ELISA quantitation kit (Bethyl Laboratories) according to the manufacturer’s protocol. BUN was measured by the urease-indophenol method with a Urea NB kit (Wako Pure Chemical Industries, Tokyo, Japan).
Statistical analysis
Values are presented as mean ± SEM. Statistical comparisons and correlation analysis were performed with the StatView program (Abacus Concepts, Berkeley, CA) using the Mann-Whitney U test or Student’s t test as appropriate. A p value of <0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As alluded to earlier, two DAF genes are known to exist in the
mouse (22, 24). To examine the respective expression of
the GPI-DAF and TM-DAF genes in the wild-type
mouse kidney and the possibility that compensatory expression of the
TM-DAF gene might have occurred in the GPI-DAF
knockout mouse kidney, Northern blot analysis using cDNA probes
specific to either the GPI-DAF mRNA or the TM-DAF mRNA were performed.
Fig. 1
A demonstrates that two
GPI-DAF mRNA species were detected in the wild-type but not in the
GPI-DAF gene knockout mouse kidney. The pattern of two
distinct mRNA species, presumably a result of alternative splicing, is
similar to that observed in other mouse tissues (23),
although the relative abundance of these messages does vary from tissue
to tissue (23). No TM-DAF mRNA was detected in either the
wild-type or the GPI-DAF gene knockout mouse kidney. This
result suggests that the TM-DAF gene is not expressed in the
mouse kidney and that the GPI-DAF knockout mouse is
completely deficient of DAF expression in the kidney.
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To determine whether there was compensatory expression of
Crry in the DAF knockout mouse kidney, we performed Western
blot analysis of membrane protein extracts of kidneys using a rat
anti-mouse Crry mAb. Fig. 1
B shows that there is no
significant difference in Crry protein levels between wild-type and
knockout mouse kidneys or between male and female mouse kidneys.
Because we observed in our preliminary experiments a gender difference
in the sensitivity of glomerulonephritis development, we also
investigated by RT-PCR whether there is a sex difference in the
expression of GPI-DAF. As shown in Fig. 1C,
RT-PCR analysis revealed no appreciable difference in
GPI-DAF expression between the male and female kidneys.
Consistent with the Western blot data (Fig. 1B), no gender
difference was detected by RT-PCR in Crry expression between
male and female kidneys (Fig. 1C).
DAF knockout mice are more susceptible to nephrotoxic serum nephritis
Preliminary experiments established the minimum and subnephritogenic doses required for nephritis (0.05 ml/20g body weight). We also observed in preliminary experiments that using this dosage, 72 ± 10% of glomeruli in knockout male mice (n = 3) showed damage, whereas 3 ± 3% of glomeruli in wild-type male mice (n = 3) were injured. Under the same conditions, 43 ± 32% of glomeruli in knockout female mice (n = 3) demonstrated damage, whereas 3 ± 6% of glomeruli in wild-type female mice (n = 3) were injured. Thus, although there was a trend of increased sensitivity in the knockout mice of both sexes, knockout males appeared to be more sensitive to nephritis development. Because male mice have higher complement activity than female mice (39, 40), we decided to use male mice only in our experiments to simplify the study.
Eight days after anti-GBM serum administration, glomeruli of DAF
knockout mice appeared enlarged and showed global glomerular
hypercellularity and segmental sclerosis at the periphery of the tuft
(Fig. 2). Furthermore, the knockout mice
had significant accumulation of mesangial matrix (Fig. 2C),
and in some cases there were completely collapsed lobules and enlarged
epithelial cells (Fig. 2D). By contrast, the kidneys of the
wild-type mice were largely intact, with patent capillaries without
increased matrix or cellularity (Fig. 2A). Fig. 3 shows the results of quantitative
analysis of the morphological changes. Both glomerular volume and the
number of cells per glomerulus were significantly increased in the DAF
knockout mice as compared with controls. Even more striking is the
increased percentage of glomeruli that showed signs of injury in the
knockout mice (Fig. 3C). Approximately 70% of knockout
glomeruli showed signs of injury whereas relatively few in the
wild-type sustained similar degree of damage (Fig. 3).
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). No wild-type
mice developed abnormal albuminuria (<0.05 mg/day). However, three of
the knockout mice with the most severe glomerular damage excreted >2
mg/day of albumin, and there was a significant correlation between
albuminuria and glomerular damage as assessed by the percentage of
glomeruli showing histological signs of injury under light microscopy
(r = 0.88, p = 0.0022).
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Potential mechanisms of increased nephritis were then explored.
Eight hours after anti-GBM serum treatment, there was prominent
deposition of rabbit as well as mouse IgG in the wild-type and knockout
kidneys (Fig. 4, top and
bottom rows). By contrast, deposition of C3 in capillary
loops of glomeruli was observed only in the knockout mouse kidneys
(Fig. 4, second row, and Table II). This was associated with fibrinogen
deposition and thrombus formation, which was detected only in the
glomeruli of the knockout mice (Fig. 4, third row, and Table II). Analysis of circulating total IgG, IgM at day 1 and rabbit
IgG-specific mouse IgG at day 7 after disease induction (i.e.,
anti-GBM administration) also revealed no significant difference
between wild-type and knockout mice (total IgG 0.47 ± 0.11 mg/ml
for wild-type, n = 5, 0.50 ± 0.11 mg/ml for
knockout, n = 8; total IgM 0.21 ± 0.02 mg/ml for
wild-type, n = 5, and 0.17 ± 0.02 mg/ml for
knockout n = 8; ELISA readings of rabbit IgG-specific
mouse IgG assay 480 ± 201 OD450 for
wild-type, n = 5, and 589 ± 442
OD450 for knockout, n = 8;
p = 0.62).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DAF is a central membrane complement regulator which in humans has been mostly studied in the context of PNH syndrome and xenotransplantation experiments (12, 47). Although a number of studies have examined the expression of DAF protein in both normal and diseased human kidneys (16, 17), the role of DAF in immune glomerulonephritis has not been adequately addressed. Investigation using animal models has been hampered by the initial slow pace in identifying the animal orthologues of human DAF in nonprimate species (7). It is now known, however, that both the rat and the mouse contain DAF genes (4), as well as a related and rodent-specific membrane complement regulator Crry (4). In fact, two DAF genes, possibly resulting from a recent gene duplication event, have been identified in the mouse (22, 24). We showed here that the GPI-DAF gene but not the TM-DAF gene is expressed in the mouse kidney. Furthermore, although the TM-DAF gene is still intact in the GPI-DAF knockout mouse (23), no compensatory expression of TM-DAF in the GPI-DAF knockout mouse kidney was observed. Thus, our GPI-DAF gene knockout mouse provides an appropriate animal model to examine the consequence of DAF deficiency in immune glomerulonephritis development.
A number of studies have demonstrated a protective role for two other
membrane regulators of complement activation, the membrane attack
complex inhibitor CD59 and the rodent-specific C3 inhibitor
Crry. For example, it has been shown that neutralization of CD59
function exacerbated complement-mediated kidney injury in the rat
(48). Similarly, in a rat model of thrombotic
microangiopathy induced by anti-endothelial cell Abs, perfusion of
animals with anti-CD59 led to more severe glomerular endothelial
damage with enhanced platelet and fibrin deposition (49).
In a related study, neutralization of rat Crry caused
tubulointerstitial injury in the kidney (50). Much
evidence in support of a protective role of Crry in immune glomerular
damage has also accumulated from studies using soluble Crry as a
systemic fluid phase inhibitor. In this regard, both administration of
a recombinant, soluble Crry systemically or overexpression of Crry in
transgenic mice was protective from Ab-induced glomerular injury
(36, 37, 38). Thus, it is especially remarkable that DAF
knockout mice were more sensitive to nephrotoxic serum,
despite normal Crry expression in the DAF knockout mouse kidney (Fig. 1). Although our finding does not exclude a protective role of
membrane-anchored Crry in this disease model, it does suggest that the
function of DAF in the mouse kidney cannot be completely compensated by
Crry in this model. The relative efficacy of protection by
membrane-anchored Crry and DAF in this disease model remains to be
defined. However, recent in vitro assays have established that, at
least in the fluid phase, recombinant mouse DAF is more active on a
molar basis than recombinant Crry as a classical pathway complement
inhibitor, whereas the reverse is true concerning their potency as
alternative pathway complement inhibitors (51).
The principal mediators responsible for the increased sensitivity of DAF knockout mice to nephrotoxic serum are not yet known. It is well recognized that immune glomerular damage can occur as a result of C3a and C5a generation or of C5b-9 deposition on kidney cells (52, 53). Because DAF inhibits C3 convertases, thus acting at an early step of the complement activation cascade, deficiency of DAF is expected to increase local C3a and C5a biosynthesis after nephrotoxic serum binding to their target Ags. Moreover, human DAF can also inhibit the activity of C5 convertase (5, 54). Thus, it is possible that increased deposition of the C5b-7 complex on resident glomerular cells will overwhelm the protective effect of CD59, resulting in increased membrane attack complex deposition and damage in the knockout kidney. Consistent with increased local C3 activation, our immunofluorescence experiments showed enhanced C3b deposition in the knockout mouse glomeruli. Fibrinogen deposition, indicating glomerular thrombosis and vascular damage, is also a hallmark of complement-mediated kidney damage and was observed in the knockout mouse glomeruli. In our pilot experiments, we found that DAF knockout females were not as sensitive to nephrotoxic serum glomerular damage as the DAF knockout males. One possible explanation for this phenomenon is that female mice may have less circulating complement activity (39, 40). A similar gender bias in complement-dependent phenotypes was also observed in a CD59 gene knockout mouse (40).
The present results that DAF-deficient mice were more sensitive to glomerulonephritis provide further evidence for the role of complement in immune-mediated glomerular damage. Although it has been generally accepted based on clinical and animal experimental data that complement plays a detrimental role in immune glomerular damage (31, 32), some recent experiments using Fc receptor knockout mice have questioned the relevance of the complement pathway in autoimmune glomerulonephritis (55, 56). In contrast, studies of C3- and C4-deficient mice have clearly demonstrated a role of complement in anti-GBM glomerulonephritis and showed that the relative contribution in the disease pathogenesis by the complement pathway is dependent on the dosage of the nephrotoxic Abs used (33). Results presented here suggest that the function of membrane complement-regulatory proteins may be another critical variable in determining the degree of complement-mediated inflammatory damage in an immune disease setting.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Wen-Chao Song, Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine,1351 BRBII/III, 421 Curie Boulevard, Philadelphia, PA 19104; or Dr. Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
3 Abbreviations used in this paper: DAF, decay-accelerating factor; MCP, membrane cofactor protein; CR1, complement receptor 1; PNH, paroxysmal nocturnal hemoglobinuria; GBM, glomerular basement membrane; BUN, blood urea nitrogen.
Received for publication February 21, 2001. Accepted for publication June 25, 2001.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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D. Turnberg, M. Botto, J. Warren, B. P. Morgan, Mark. J. Walport, and H. T. Cook CD59a Deficiency Exacerbates Accelerated Nephrotoxic Nephritis in Mice J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2271 - 2279. [Abstract] [Full Text] [PDF]
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M. Nangaku Complement Regulatory Proteins: Are They Important in Disease? J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2411 - 2413. [Full Text] [PDF]
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 H. Pavenstadt, W. Kriz, and M. Kretzler Cell Biology of the Glomerular Podocyte Physiol Rev, January 1, 2003; 83(1): 253 - 307. [Abstract] [Full Text] [PDF]
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 J. C. Mason, Z. Ahmed, R. Mankoff, E. A. Lidington, S. Ahmad, V. Bhatia, A. Kinderlerer, A. M. Randi, and D. O. Haskard Statin-Induced Expression of Decay-Accelerating Factor Protects Vascular Endothelium Against Complement-Mediated Injury Circ. Res., October 18, 2002; 91(8): 696 - 703. [Abstract] [Full Text] [PDF]
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T. Miwa, M. A. Maldonado, L. Zhou, X. Sun, H. Y. Luo, D. Cai, V. P. Werth, M. P. Madaio, R. A. Eisenberg, and W.-C. Song Deletion of Decay-Accelerating Factor (CD55) Exacerbates Autoimmune Disease Development in MRL/lpr Mice Am. J. Pathol., September 1, 2002; 161(3): 1077 - 1086. [Abstract] [Full Text] [PDF]
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