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1.  Membranous nephropathy: from models to man 
The Journal of Clinical Investigation  2014;124(6):2307-2314.
As recently as 2002, most cases of primary membranous nephropathy (MN), a relatively common cause of nephrotic syndrome in adults, were considered idiopathic. We now recognize that MN is an organ-specific autoimmune disease in which circulating autoantibodies bind to an intrinsic antigen on glomerular podocytes and form deposits of immune complexes in situ in the glomerular capillary walls. Here we define the clinical and pathological features of MN and describe the experimental models that enabled the discovery of the major target antigen, the M-type phospholipase A2 receptor 1 (PLA2R). We review the pathophysiology of experimental MN and compare and contrast it with the human disease. We discuss the diagnostic value of serological testing for anti-PLA2R and tissue staining for the redistributed antigen, and their utility for differentiating between primary and secondary MN, and between recurrent MN after kidney transplant and de novo MN. We end with consideration of how knowledge of the antigen might direct future therapeutic strategies.
PMCID: PMC4089468  PMID: 24892704
2.  Inhibitory Effects of Robo2 on Nephrin: A Crosstalk between Positive and Negative Signals Regulating Podocyte Structure 
Cell reports  2012;2(1):52-61.
Robo2 is the cell surface receptor for the repulsive guidance cue Slit and is involved in axon guidance and neuronal migration. Nephrin is a podocyte slit-diaphragm protein that functions in the kidney glomerular filtration barrier. Here we report that Robo2 is expressed at the basal surface of mouse podocytes and co-localizes with nephrin. Biochemical studies indicate that Robo2 forms a complex with nephrin in the kidney through adaptor protein Nck. In contrast to the role of nephrin that promotes actin polymerization, Slit2-Robo2 signaling inhibits nephrin-induced actin polymerization. In addition, the amount of F-actin associated with nephrin is increased in Robo2 knockout mice that develop an altered podocyte foot process structure. Genetic interaction study further reveals that loss of Robo2 alleviates the abnormal podocyte structural phenotype in nephrin null mice. These results suggest that Robo2 signaling acts as a negative regulator on nephrin to influence podocyte foot process architecture.
PMCID: PMC3627357  PMID: 22840396
3.  Coexistence of ANCA-associated glomerulonephritis and anti-phospholipase A2 receptor antibody-positive membranous nephropathy 
Clinical Kidney Journal  2012;5(2):162-165.
Antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) have been demonstrated to mediate anti-neutrophil cytoplasmic antibody (ANCA)-associated disease. For membranous nephropathy, antibodies to the podocyte-expressed phospholipase A2 receptor (anti-PLA2R) are highly associated with disease activity and have been reported in at least 70% of patients with idiopathic membranous nephropathy (IMN). We present a case of a 56-year-old male with a 1 year history of hypertension, leg edema, and proteinuria, who presented with advanced renal failure and was found to have both ANCA-associated glomerulonephritis (GN) and IMN on kidney biopsy. Consistent with the idea that this is due to the chance occurrence of two independent diseases, we found both anti-MPO and anti-PLA2R antibodies in the patient's sera. Treatment with methylprednisolone, plasmapheresis, and cyclophosphamide resulted in improvement in kidney function and proteinuria, together with the simultaneous decrease in both autoantibodies. This is the first demonstration of two pathogenic antibodies giving rise to ANCA-associated GN and IMN in the same patient. It confirms the importance of classifying disease based upon the underlying mechanism, in addition to renal histopathology, to both optimize therapy and predict prognosis.
PMCID: PMC3341840  PMID: 22833809
ANCA vasculitis; antiphospholipase; membranous nephropathy
4.  IgG4-Related Disease Is Not Associated with Antibody to the Phospholipase A2 Receptor 
Patients with IgG4-related disease (IgG4-RD) share histopathological characteristics that are similar across affected organs. The finding of infiltration with IgG4+ plasma cells in the proper clinical and histopathological contexts connects a large number of clinical entities that were viewed previously as separate conditions. The renal involvement in IgG4-RD is usually characterized by tubulointerstitial nephritis, but membranous nephropathy has also been reported to be one of the renal complications of IgG4-RD. The recent discovery that a high proportion of patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies to the M-type phospholipase A2 receptor (PLA2R) in the circulation and glomerular immune deposits, together with the profound IgG4 hypergammaglobulinemia and occasional reports of membranous nephropathy in IgG4-RD, raised the question of a common antigen. To assess the presence of anti-PLA2R antibody in patients with IgG4-RD, we screened sera from 28 IgG4-RD patients by immunoblot. None of the patients in this cohort had detectable circulating anti-PLA2R antibodies. This study suggests that despite some clinical and serological overlaps between IgG4-RD and IMN,anti-PLA2R antibodies do not play a role in the pathogenesis of IgG4-RD. Additional studies of IgG4-RD with evidence of membranous nephropathy are important to exclude any definite relationship.
PMCID: PMC3357948  PMID: 22654915
5.  The Epidermal Growth Factor Receptor Promotes Glomerular Injury and Renal Failure in Rapidly Progressive Crescentic Glomerulonephritis; the Identification of Possible Therapy 
Nature Medicine  2011;17(10):1242-1250.
Rapidly progressive glomerulonephritis (RPGN) is a clinical a morphological expression of severe glomerular injury. Glomerular injury manifests as a proliferative histological pattern (“crescents”) with accumulation of T cells and macrophages, and proliferation of intrinsic glomerular cells. We show de novo induction of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in intrinsic glomerular epithelial cells (podocytes) from both mice and humans with RPGN. HB-EGF induction increases phosphorylation of the EGFR/ErbB1 receptor in mice with RPGN. In HB-EGF-deficient mice, EGFR activation in glomeruli is absent and the course of RPGN is improved. Autocrine HB-EGF induces a phenotypic switch in podocytes in vitro. Conditional deletion of the Egfr gene from podocytes of mice alleviates the severity of RPGN. Pharmacological blockade of EGFR also improves the course of RPGN, even when started 4 days after the induction of experimental RPGN. This suggests that targeting the HB-EGF/EGFR pathway could also be beneficial for treatment of human RPGN.
PMCID: PMC3198052  PMID: 21946538
6.  Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease 
The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for lamellipodial protrusion. This process required a PI3K-, Cas-, and Crk1/2-dependent signaling mechanism distinct from the previously described nephrin-Nck1/2 pathway necessary for assembly and polymerization of actin filaments. Our present findings also support the hypothesis that mechanisms governing lamellipodial protrusion in culture are similar to those used in vivo during foot process effacement in a subset of glomerular diseases. In mice, podocyte-specific deletion of Crk1/2 prevented foot process effacement in one model of podocyte injury and attenuated foot process effacement and associated proteinuria in a delayed fashion in a second model. In humans, focal adhesion kinase and Cas phosphorylation — markers of focal adhesion complex–mediated Crk-dependent signaling — was induced in minimal change disease and membranous nephropathy, but not focal segmental glomerulosclerosis. Together, these observations suggest that activation of a Cas-Crk1/2–dependent complex is necessary for foot process effacement observed in distinct subsets of human glomerular diseases.
PMCID: PMC3266791  PMID: 22251701
7.  Noninvasive Assessment of Antenatal Hydronephrosis in Mice Reveals a Critical Role for Robo2 in Maintaining Anti-Reflux Mechanism 
PLoS ONE  2011;6(9):e24763.
Antenatal hydronephrosis and vesicoureteral reflux (VUR) are common renal tract birth defects. We recently showed that disruption of the Robo2 gene is associated with VUR in humans and antenatal hydronephrosis in knockout mice. However, the natural history, causal relationship and developmental origins of these clinical conditions remain largely unclear. Although the hydronephrosis phenotype in Robo2 knockout mice has been attributed to the coexistence of ureteral reflux and obstruction in the same mice, this hypothesis has not been tested experimentally. Here we used noninvasive high-resolution micro-ultrasonography and pathological analysis to follow the progression of antenatal hydronephrosis in individual Robo2-deficient mice from embryo to adulthood. We found that hydronephrosis progressed continuously after birth with no spontaneous resolution. With the use of a microbubble ultrasound contrast agent and ultrasound-guided percutaneous aspiration, we demonstrated that antenatal hydronephrosis in Robo2-deficient mice is caused by high-grade VUR resulting from a dilated and incompetent ureterovesical junction rather than ureteral obstruction. We further documented Robo2 expression around the developing ureterovesical junction and identified early dilatation of ureteral orifice structures as a potential fetal origin of antenatal hydronephrosis and VUR. Our results thus demonstrate that Robo2 is crucial for the formation of a normal ureteral orifice and for the maintenance of an effective anti-reflux mechanism. This study also establishes a reproducible genetic mouse model of progressive antenatal hydronephrosis and primary high-grade VUR.
PMCID: PMC3176762  PMID: 21949750
8.  Methylation determines fibroblast activation and fibrogenesis in the kidney 
Nature medicine  2010;16(5):544-550.
Fibrogenesis is a pathological wound repair process that fails to cease, even when the initial insult has been removed. Fibroblasts are principal mediators of fibrosis, and fibroblasts from fibrotic tissues fail to return to their quiescent stage, including when cultured in vitro. In a search for underlying molecular mechanisms, we hypothesized that this perpetuation of fibrogenesis is caused by epigenetic modifications. We demonstrate here that hypermethylation of RASAL1, encoding an inhibitor of the Ras oncoprotein, is associated with the perpetuation of fibroblast activation and fibrogenesis in the kidney. RASAL1 hypermethylation is mediated by the methyltransferase Dnmt1 in renal fibrogenesis, and kidney fibrosis is ameliorated in Dnmt1+/− heterozygous mice. These studies demonstrate that epigenetic modifications may provide a molecular basis for perpetuated fibroblast activation and fibrogenesis in the kidney.
PMCID: PMC3106179  PMID: 20418885
9.  Nephritogenic mAb 5-1-6 is directed at the extracellular domain of rat nephrin 
Journal of Clinical Investigation  1999;104(11):1559-1566.
mAb 5-1-6 identifies an antigen on rat podocyte slit-diaphragms and induces severe proteinuria when injected into rats. Nephrin, an Ig-like transmembrane protein that is mutated in congenital nephrotic syndrome of the Finnish type, has been localized to the slit-diaphragm on human podocytes. Here we document that the mAb 5-1-6 antigen is rat nephrin. After incubation of rat glomeruli with this mAb, the antibody/antigen complex was chemically cross-linked, extracted, and immunoprecipitated, prior to Western analysis. By mass spectrometry and 2D gel electrophoresis, we identified several peptides with complete identity to human nephrin. In addition, the 185-kDa protein immunoprecipitated by mAb 5-1-6 from rat glomerular extracts reacts with a rabbit anti-mouse nephrin antibody. Finally, nephrin and the mAb 5-1-6 antigen have identical glomerular localization patterns on immunofluorescence of rat kidney. These results demonstrate that the nephritogenic mAb 5-1-6 identifies the extracellular domain of nephrin, thereby documenting the importance of the slit-diaphragm and its component, nephrin, in the regulation of glomerular permselectivity.
J. Clin. Invest. 104:1559–1566 (1999).
PMCID: PMC409863  PMID: 10587519
10.  M-Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous Nephropathy 
Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown.
We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody.
Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in non-reduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A2 receptor (PLA2R). Reactive serum specimens recognized recombinant PLA2R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA2R antibody. Anti-PLA2R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA2R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA2R.
A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA2R. PLA2R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA2R is a major antigen in this disease.
PMCID: PMC2762083  PMID: 19571279
11.  Experimental membranous nephropathy redux 
Membranous nephropathy (MN) is a common cause of nephrotic syndrome in adults. Active and passive Heymann nephritis (HN) in rats are valuable experimental models because their features so closely resemble human MN. In HN, subepithelial immune deposits form in situ as a result of circulating antibodies. Complement activation leads to assembly of C5b-9 on glomerular epithelial cell (GEC) plasma membranes and is essential for sublethal GEC injury and the onset of proteinuria. This review revisits HN and focuses on areas of substantial progress in recent years. The response of the GEC to sublethal C5b-9 attack is not simply due to disruption of the plasma membrane but is due to the activation of specific signaling pathways. These include activation of protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress proteins, proteinases, and others. Ultimately, these signals impact on cell metabolic pathways and the structure/function of lipids and key proteins in the cytoskeleton and slit-diaphragm. Some signals affect GEC adversely. Thus C5b-9 induces partial dissolution of the actin cytoskeleton. There is a decline in nephrin expression, reduction in F-actin-bound nephrin, and loss of slit-diaphragm integrity. Other signals, such as endoplasmic reticulum stress, may limit complement-induced injury, or promote recovery. The extent of complement activation and GEC injury is dependent, in part, on complement-regulatory proteins, which act at early or late steps within the complement cascade. Identification of key steps in complement activation, the cellular signaling pathways, and the targets will facilitate therapeutic intervention in reversing GEC injury in human MN.
PMCID: PMC1325222  PMID: 16159900
passive Heymann nephritis; podocyte; complement; complement regulation; proteinuria; autoimmunity; cell signaling; cytoskeleton; slit-diaphragm
12.  Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes 
Journal of Clinical Investigation  2004;114(5):679-688.
Anti-C1q autoantibodies are present in sera of patients with several autoimmune diseases, including systemic lupus erythematosus (SLE). Strikingly, in SLE the presence of anti-C1q is associated with the occurrence of nephritis. We have generated mouse anti–mouse C1q mAb’s and used murine models to investigate whether anti-C1q autoantibodies actually contribute to renal pathology in glomerular immune complex disease. Administration of anti-C1q mAb JL-1, which recognizes the collagen-like region of C1q, resulted in glomerular deposition of C1q and anti-C1q autoantibodies and mild granulocyte influx, but no overt renal damage. However, combination of JL-1 with a subnephritogenic dose of C1q-fixing anti–glomerular basement membrane (anti-GBM) antibodies enhanced renal damage characterized by persistently increased levels of infiltrating granulocytes, major histological changes, and increased albuminuria. This was not observed when a non–C1q-fixing anti-GBM preparation was used. Experiments with different knockout mice showed that renal damage was dependent not only on glomerular C1q and complement activation but also on Fcγ receptors. In conclusion, anti-C1q autoantibodies deposit in glomeruli together with C1q but induce overt renal disease only in the context of glomerular immune complex disease. This provides an explanation why anti-C1q antibodies are especially pathogenic in patients with SLE.
PMCID: PMC514584  PMID: 15343386
13.  Essential role of Gas6 for glomerular injury in nephrotoxic nephritis 
Growth-arrest specific gene 6 (Gas6) is a vitamin K–dependent growth factor for mesangial and epithelial cells. To investigate whether Gas6 is essential for progressive glomerular injury, we constructed Gas6–/– mice and examined the role of Gas6 in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis. We found less mortality and proteinuria in Gas6–/– mice than in wild-type mice following injection of nephrotoxic serum. Glomerular cell proliferation, glomerular sclerosis, crescent formation, and deposition of fibrin/fibrinogen in glomeruli were also reduced in Gas6–/– mice. Furthermore, administering Gas6–/– mice recombinant wild-type Gas6, but not Gas6 lacking a previously characterized N-terminal γ-carboxyl group, induced massive proteinuria, glomerular cell proliferation, and glomerulosclerosis, comparable to responses seen in wild-type mice. These data indicate that Gas6 induces glomerular cell proliferation in NTN and suggest that this factor contributes to glomerular injury and the progression of chronic nephritis.
PMCID: PMC151046  PMID: 12122116
14.  IL-15, a survival factor for kidney epithelial cells, counteracts apoptosis and inflammation during nephritis 
IL-15, a T cell growth factor, has been linked to exacerbating autoimmune diseases and allograft rejection. To test the hypothesis that IL-15–deficient (IL-15–/–) mice would be protected from T cell–dependent nephritis, we induced nephrotoxic serum nephritis (NSN) in IL-15–/– and wild-type (IL-15+/+) C57BL/6 mice. Contrary to our expectations, IL-15 protects the kidney during this T cell–dependent immunologic insult. Tubular, interstitial, and glomerular pathology and renal function are worse in IL-15–/– mice during NSN. We detected a substantial increase in tubular apoptosis in IL-15–/– kidneys. Moreover, macrophages and CD4 T cells are more abundant in the interstitia and glomeruli in IL-15–/– mice. This led us to identify several mechanisms responsible for heightened renal injury in the absence of IL-15. We now report that IL-15 and the IL-15 receptor (α, β, γ chains) are constitutively expressed in normal tubular epithelial cells (TECs). IL-15 is an autocrine survival factor for TECs. TEC apoptosis induced with anti-Fas or actinomycin D is substantially greater in IL-15–/– than in wild-type TECs. Moreover, IL-15 decreases the induction of a nephritogenic chemokine, MCP-1, that attracts leukocytes into the kidney during NSN. Taken together, we suggest that IL-15 is a therapeutic for tubulointerstitial and glomerular kidney diseases.
PMCID: PMC150930  PMID: 11927622
15.  Targeted deletion of CX3CR1 reveals a role for fractalkine in cardiac allograft rejection 
Journal of Clinical Investigation  2001;108(5):679-688.
Fractalkine (Fk) is a structurally unusual member of the chemokine family. To determine its role in vivo, we generated mice with a targeted disruption of CX3CR1, the receptor for Fk. CX3CR1–/– mice were phenotypically indistinguishable from wild-type mice in a pathogen-free environment. In response to antibody-induced glomerulonephritis, CX3CR1–/– and CX3CR1+/+ mice had similar levels of proteinuria and injury. CX3CR1–/– and CX3CR1+/+ mice also developed similar levels of disease in myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis. We performed heterotopic MHC class I/II cardiac transplants from BALB/c mice into C57BL/6 mice. In the absence of cyclosporin A (CsA), there was no difference in graft survival time between CX3CR1–/– and CX3CR1+/+ recipient mice. However, in the presence of subtherapeutic levels of CsA, graft survival time was significantly increased in the CX3CR1–/– mice. Characterization of cells infiltrating the grafts revealed a selective reduction in natural killer cells in the CX3CR1–/– recipients in the absence of CsA and a reduction in macrophages, natural killer cells, and other leukocytes in the presence of CsA. We conclude that Fk plays an important role in graft rejection. The development of CX3CR1 antagonists may allow reductions in the doses of immunosuppressive drugs used in transplantation.
PMCID: PMC209384  PMID: 11544273
17.  Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis 
Journal of Clinical Investigation  1999;104(11):1549-1557.
During the development of nephrotoxic nephritis (NTN) in the mouse, we find that a variety of chemokines and chemokine receptors are induced: CCR1 (RANTES, MIP-1α), CCR2 (MCP-1), CCR5 (RANTES, MIP-1α, MIP-1β), CXCR2 (MIP-2), and CXCR3 (IP-10). Their timing of expression indicated that CXCR2 and CCR1 are probably important in the neutrophil-dependent heterologous phase of the disease, whereas CCR1, CCR2, CCR5, and CXCR3 accompany the subsequent mononuclear cell infiltration characteristic of autologous disease. We therefore assessed the role of CCR1 in NTN using CCR1–/– mice. We found that neutrophil accumulation in CCR1–/– mice was comparable to that in wild-type animals but that renal recruitment of CD4+ and CD8+ T cells and macrophages increased significantly. Moreover, CCR1–/– mice developed more severe glomerulonephritis than did controls, with greater proteinuria and blood urea nitrogen, as well as a higher frequency of crescent formation. In addition, CCR1–/– mice showed enhanced Th1 immune responses, including titers of antigen-specific IgG2a antibody, delayed-type hypersensitivity responses, and production of IFN-γ and TNF-α. Lastly, using recombinant proteins and transfected cells that overexpressed CCR1, we demonstrated that MIP-1α, but not RANTES, bound CCR1 and induced cell chemotaxis. Thus, rather than simply promoting leukocyte recruitment during NTN, CCR1 expression profoundly alters the effector phase of glomerulonephritis. Therapeutic targeting of chemokine receptors may, on occasion, exacerbate underlying disease.
J. Clin. Invest. 104:1549–1557 (1999).
PMCID: PMC409862  PMID: 10587518
18.  Inhibition of Complement Regulation Is Key to the Pathogenesis of Active Heymann Nephritis  
The Journal of Experimental Medicine  1998;188(7):1353-1358.
Crry (complement receptor 1–related protein/gene y) is a key cellular complement regulator in rodents. It is also present in Fx1A, the renal tubular preparation used to immunize rats to induce active Heymann nephritis (HN), a model of membranous nephropathy. We hypothesized that rats immunized with anti-Fx1A develop autoantibodies (auto-Abs) to Crry as well as to the megalin-containing HN antigenic complex, and that anti-Crry Abs promote the development of injury in HN by neutralizing the complement regulatory activity of Crry. Rats immunized with Fx1A lacking Crry remained free of proteinuria and glomerular deposits of C3 during a 10-wk follow-up despite typical granular immunoglobulin (Ig)G deposits in glomeruli. Anti-Fx1A auto-Abs were present in their sera at levels that were not different from sera pooled from proteinuric rats with HN induced with nephritogenic Fx1A. Passive administration of sheep anti-Crry Abs to rats immunized with Crry-deficient Fx1A led to proteinuria and glomerular C3 deposition, which were not seen in such rats injected with preimmune IgG, nor in rats with collagen-induced arthritis injected with anti-Crry IgG. To directly examine the role of Crry in HN, rats were immunized with Crry-deficient Fx1A reconstituted with rCrry. This led to typical HN, with 8 out of 15 rats developing proteinuria within 14 wk. Moreover, the extent of glomerular C3 deposition correlated with proteinuria, and anti-Crry Abs were present in glomerular eluates. Thus, Crry is a key nephritogenic immunogen in Fx1A. Formation of neutralizing auto-Abs to Crry impairs its function, leading to unrestricted complement activation by Abs reactive with the HN antigenic complex on the epithelial cell surface.
PMCID: PMC2212493  PMID: 9763614
complement regulation; Heymann nephritis; Crry; autoantibodies; glomerulus
19.  RANTES and Monocyte Chemoattractant Protein–1 (MCP-1) Play an Important Role in the Inflammatory Phase of Crescentic Nephritis, but Only MCP-1 Is Involved in Crescent Formation and Interstitial Fibrosis 
The Journal of Experimental Medicine  1997;185(7):1371-1380.
The involvement of chemokines in inflammation is well established, but their functional role in disease progression, and particularly in the development of fibrosis, is not yet understood. To investigate the functional role that the chemokines monocyte chemoattractant protein–1 (MCP-1) and RANTES play in inflammation and the progression to fibrosis during crescentic nephritis we have developed and characterized a murine model for this syndrome. Significant increases in T-lymphocytes and macrophages were observed within glomeruli and interstitium, paralleled by an induction of mRNA expression of MCP-1 and RANTES, early after disease initiation. Blocking the function of MCP-1 or RANTES resulted in significant decreases in proteinuria as well as in numbers of infiltrating leukocytes, indicating that both MCP-1 and RANTES (regulated upon activation in normal T cells expressed and secreted) play an important role in the inflammatory phase of crescentic nephritis. In addition, neutralization of MCP-1 resulted in a dramatic decrease in both glomerular crescent formation and deposition of type I collagen. These results highlight a novel role for MCP-1 in crescent formation and development of interstitial fibrosis, and indicate that in addition to recruiting inflammatory cells this chemokine is critically involved in irreversible tissue damage.
PMCID: PMC2196251  PMID: 9104823
20.  Experimental Membranous Glomerulonephritis in Rats 
Quantitation of immune deposit formation in glomeruli and correlation with immunohistologic and functional changes has been accomplished only in models of anti-glomerular basement membrane antibody-induced nephritis, or indirectly in immune complex disease by measuring radiolabeled antigen deposition. The kinetics of subepithelial immune deposit formation and the relationship between the quantity of antibody deposited and proteinuria are defined here for the first time in an established model of membranous immune complex nephritis (passive Heymann nephritis) induced by a single intravenous injection of 125I-labeled sheep immunoglobulin (Ig)G antibody to rat tubular brush border antigen (Fx1A). Measurement of antibody deposition in glomeruli (GAb) isolated from rats injected with 10 mg of anti-Fx1A demonstrated a mean of 12 μg GAb in 4 h, which increased linearly to 48 μg in 5 d. GAb represented only 20 and 44% of total kidney antibody binding at these times. Proteinuria occurred only after 4-5 d of antibody deposition in rats with total kidney antibody binding exceeding ∼200 μg/2 kidneys. Steroid treatment and vasoactive amine blockade did not significantly alter the quantity or localization of immune deposits. It was also demonstrated that isolated rat glomeruli specifically bound nephritogenic quantities of anti-Fx1A in vitro within hours. Analysis of the quantitative aspects of glomerular antibody deposition in vivo and glomerular antibody binding in vitro provides additional evidence that subepithelial immune deposits in passive Heymann nephritis may form in situ by reaction of free antibody with antigenic constitutents of the normal rat glomerulus. The observed kinetics of deposit formation differ markedly from those in anti-glomerular basement membrane disease and suggest a role for factors in addition to antigen-antibody interaction in determining this unique pattern of glomerular immune deposit formation.
PMCID: PMC371507  PMID: 7400310

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