[Show abstract][Hide abstract] ABSTRACT: Renal fibrosis and inflammation are associated with hypoxia, and tissue pO(2) plays a central role in modulating the progression of chronic kidney disease. Key mediators of cellular adaptation to hypoxia are hypoxia-inducible factor (HIF)-1 and -2. In the kidney, they are expressed in a cell type-specific manner; to what degree activation of each homolog modulates renal fibrogenesis and inflammation has not been established. To address this issue, we used Cre-loxP recombination to activate or to delete both Hif-1 and Hif-2 either globally or cell type specifically in myeloid cells. Global activation of Hif suppressed inflammation and fibrogenesis in mice subjected to unilateral ureteral obstruction, whereas activation of Hif in myeloid cells suppressed inflammation only. Suppression of inflammatory cell infiltration was associated with downregulation of CC chemokine receptors in renal macrophages. Conversely, global deletion or myeloid-specific inactivation of Hif promoted inflammation. Furthermore, prolonged hypoxia suppressed the expression of multiple inflammatory molecules in noninjured kidneys. Collectively, we provide experimental evidence that hypoxia and/or myeloid cell-specific HIF activation attenuates renal inflammation associated with chronic kidney injury.
The Journal of Immunology 04/2012; 188(10):5106-15. · 5.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polyomavirus-associated nephropathy (PVAN) is a significant complication after kidney transplantation, often leading to premature graft loss. In order to identify antiviral responses of the renal tubular epithelium, we studied activation of the viral DNA and the double-stranded RNA (dsRNA) sensors Toll-like receptor 3 (TLR3) and retinoic acid inducible gene-I (RIG-I) in allograft biopsy samples of patients with PVAN, and in human collecting duct cells in culture after stimulation by the dsRNA mimic polyriboinosinic:polyribocytidylic acid (poly(I:C)), cytokines, or infection with BK virus. Double staining using immunofluorescence for BK virus and TLR3 showed strong signals in epithelial cells of distal cortical tubules and the collecting duct. In biopsies microdissected to isolate tubulointerstitial lesions, TLR3 but not RIG-I mRNA expression was found to be increased in PVAN. Collecting duct cells in culture expressed TLR3 intracellularly, and activation of TLR3 and RIG-I by poly(I:C) enhanced expression of cytokine, chemokine, and IFN-β mRNA. This inflammatory response could be specifically blocked by siRNA to TLR3. Finally, infection of the collecting duct cells with BK virus enhanced the expression of cytokines and chemokines. This led to an efficient antiviral immune response with TLR3 and RIG-I upregulation without activation of IL-1β or components of the inflammasome pathway. Thus, PVAN activation of innate immune defense mechanisms through TLR3 is involved in the antiviral and anti-inflammatory response leading to the expression of proinflammatory cytokines and chemokines.
Kidney International 09/2011; 81(1):100-11. · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Spontaneous peritonitis is a rather rare event, even in peritoneal dialysis (PD). As defensins are natural antimicrobial peptides, we hypothesized that adipocytes as the major constituents of the omentum could play an important role in protecting against infection by generating defensin (DEFA1-3).
We isolated adipocytes from the omentum majus and conducted qualitative and quantitative RT-PCR and immunohistochemical analyses.
For the first time described, we were able to detect DEFA1-3 mRNA in highly purified isolated omental adipocytes. The expression of DEFA1-3 in adipocytes was confirmed on the protein level by immunohistochemistry.
Our report of DEFA1-3 expression by human omental adipocytes adds to the role of adipocytes in the primary defense against bacterial infection. This may include PD, where the presence of the catheter as a foreign body and the nonphysiological dialysis solution may require constant defense measures to prevent peritonitis, a hypothesis that will require further testing.
[Show abstract][Hide abstract] ABSTRACT: In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1alpha only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC.
American Journal Of Pathology 12/2009; 176(2):594-607. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chemokine (C-C motif) receptor 5 (CCR5) has been implicated in experimental and clinical allograft rejection. To dissect the function of CCR5 in acute and chronic renal allograft rejection, bilaterally nephrectomized WT and Ccr5-/- C57BL/6 mice were used as recipients of WT BALB/c renal allografts and analyzed 7 and 42 days after transplantation. Lesion scores (glomerular damage, vascular rejection, tubulointerstitial inflammation) and numbers of CD4+, CD8+, CD11c+ and alpha smooth muscle actin (alphaSMA)+ cells were reduced in allografts from Ccr5-/- recipients during the chronic phase. Increasing creatinine levels indicated deterioration of allograft function over time. While mRNA expression of Th1-associated markers decreased between 7 and 42 days, Th2-associated markers increased. Markers for alternatively activated macrophages (arginase 1, chitinase 3-like 3, resistin-like alpha, mannose receptor, C type 1), were strongly upregulated (mRNA and/or protein level) only in allografts from Ccr5-/- recipients at 42 days. Ccr5 deficiency shifted intragraft immune responses during the chronic phase towards the Th2 type and led to accumulation of alternatively activated macrophages. Additionally, splenocytes from unchallenged Ccr5-/- mice showed significantly increased arginase 1 and mannose receptor 1 mRNA levels, suggesting constitutive alternative activation of splenic macrophages. We conclude that Ccr5 deficiency favors alternative macrophage activation. This finding may be relevant for other inflammatory diseases that involve macrophage activation and may also influence future therapeutic strategies targeting CCR5.
European Journal of Immunology 10/2009; 40(1):267-78. · 4.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Duffy antigen/receptor for chemokines (DARC) is a chemokine-binding protein that is expressed on erythrocytes and renal endothelial cells. DARC-mediated endothelial transcytosis of chemokines may facilitate the renal recruitment of macrophages and T cells, as has been suggested for neutrophils. We studied the role of Darc in two mouse models of prolonged renal inflammation, one that primarily involves the tubulointerstitium (unilateral ureteral obstruction), and one that requires an adaptive immune response that leads to glomerulonephritis (accelerated nephrotoxic nephritis). Renal expression of Darc and its ligands was increased in both models. Leukocytes effectively infiltrated obstructed kidneys in Darc-deficient mice with pronounced T-cell infiltration at early time points. Development of interstitial fibrosis was comparable in both genotypes. Nephrotoxic nephritis was inducible in Darc-deficient mice, with both an increased humoral immune response and functional impairment during the early phase of disease. Leukocytes efficiently infiltrated kidneys of Darc-deficient mice, with increased cell numbers at early but not late time points. Taken together, renal inflammation developed more rapidly in DARC-deficient mice, without affecting the extent of renal injury at later time points. Thus, genetic elimination of Darc in mice does not prevent the development of renal infiltrates and may even enhance such development during the early phases of interstitial and glomerular diseases in mouse models of prolonged renal inflammation.
American Journal Of Pathology 08/2009; 175(1):119-31. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mesangial cells and their matrix form the central stalk of the glomerulus and are part of a functional unit interacting closely with endothelial cells and podocytes. Alterations in one cell type can produce changes in the others. The cytokines generated by mesangial cells, endothelial cells, and podocytes that tridirectionally and interactively influence cognate receptors on receiver cells are not fully defined. The existence of cytokine cross-talk seems very likely, given the observations that podocyte injury frequently results in mesangial cell proliferation, whereas mesangial cell injury leads to foot process fusion and proteinuria. Another potentially fruitful area of future research is the role of mesangial cells as local modulators of innate and adaptive immune responses. Thus, mesangial cell research still holds much promise.
Journal of the American Society of Nephrology 07/2009; 20(6):1179-87. · 8.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The chemokine receptors CCR2 and CCR5 represent potential novel therapeutic targets to treat important inflammatory and infectious diseases, including atherosclerosis and HIV infection. To study the functions of both receptors in vivo, we aimed to generate Ccr2/Ccr5 double-deficient mice. As these genes are separated by <20 kb, they were inactivated consecutively by two rounds of gene targeting in embryonic stem (ES) cells. Thereby neomycin and hygromycin selection cassettes flanked by four identical loxP recognition sequences for Cre recombinase were integrated into the ES cell genome together with EGFP and DsRed2 reporter genes. Both selection cassettes could be deleted in vitro by transiently transfecting ES cells with Cre expression vectors. However, after blastocyst microinjection these cells yielded only weak chimeras, and germline transmission was not achieved. Therefore, Ccr2/Ccr5 double-deficient mice were generated from ES cells still carrying both selection cassettes. Microinjection of zygotes with a recombinant fusion protein consisting of maltose-binding protein and Cre (MBP-Cre) allowed the selective deletion of both cassettes. All sequences in between and both reporter genes were left intact. Deletion of both selection cassettes resulted in enhanced DsRed2 reporter gene expression. Cre protein microinjection of zygotes represents a novel approach to perform complex recombination tasks.
[Show abstract][Hide abstract] ABSTRACT: The endoplasmic reticulum (ER) is an important site for protein folding and becomes "stressed" when its capacity to fold proteins is overwhelmed. In response, "unfolded protein response" (UPR) genes are induced, increasing the capacity to fold proteins; if the response is insufficient, then apoptosis ensues. For investigation of whether proteinuria and hyperglycemia induce ER stress in renal epithelial cells, microarray data from biopsies of established diabetic nephropathy (DN) were analyzed. Expression of UPR genes was significantly different in these biopsies than in control kidneys or biopsies of patients with mild DN, suggesting an association between the degree of DN and UPR gene expression. Expression of the transcription factor XBP1 and the ER chaperones HSPA5 and HYOU1 were increased, but the proapoptotic gene DDIT3 was unchanged. These findings were replicated in an independent cohort of patients with established DN by real-time reverse transcriptase-PCR. Immunofluorescence of renal biopsies from patients with DN confirmed the upregulation for HSPA5 and HYOU1 proteins in tubular epithelia. In biopsies of minimal-change disease, the mRNA levels of some ER stress molecules were also induced, but protein expression of HSPA5 and HYOU1 remained significantly lower than that observed in DN. Exposure of renal tubular epithelial cells to albumin and high glucose in vitro enhanced expression of genes involved in ER stress. These observations suggest that in proteinuric diseases, tubular epithelial cells undergo ER stress, which induces an adaptive, protective UPR. Although this may protect the cells from ER stress, persistence of hyperglycemia and proteinuria may eventually lead to apoptosis.
Journal of the American Society of Nephrology 10/2008; 19(11):2225-36. · 8.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Macrophages and dendritic cells are heterogenous and highly plastic bone marrow-derived cells that play major roles in renal diseases. We characterized these cells using immunohistochemistry in 55 renal biopsies from control patients or patients with glomerulonephritis as an initial step towards postulating specific roles for these cells in kidney disease. In proliferative glomerulonephritis numerous CD68 positive (pan monocyte, macrophage and dendritic marker) cells were found in both glomeruli and the tubulointerstitial space, however, a myeloid dendritic cell marker (DC-SIGN) was identified only in the tubulointerstitium. A significant number of plasmacytoid dendritic cells (identified as BDCA-2 positive cells) were seen at sites of interstitial inflammation, including follicular aggregates of inflammatory cells. Langerin positive cells (a marker of Langerhans' cells) were detectable but rare. The area of either CD68 or DC-SIGN positive interstitial cells correlated with serum creatinine. Low levels of DC-SIGN, DC-LAMP and MHC class II mRNA were present in the tubulointerstitial space in controls and increased only in that region in proliferative glomerulonephritis. We demonstrate that the CD68 positive cells infiltrating the glomerulus lack dendritic cell markers (reflecting macrophages), whereas in the tubulointerstitial space the majority of CD68 positive cells are also DC-SIGN positive (reflecting myeloid dendritic cells). Their number correlated with serum creatinine, which further emphasizes the significance of interstitial DCs in progressive glomerular diseases.
Kidney International 08/2008; 74(1):37-46. · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: B lymphocytes are part of the inflammatory cells recruited to the human kidney in various disease settings. B cell infiltrates have been described in renal allografts, in acute and chronic interstitial nephritis, and the most common glomerular diseases like immunoglobulin A (IgA) and membranous nephropathy. These cells are almost exclusively recruited to the tubulointerstitium, but not the glomerular tuft. In addition to diffuse tubulointerstitial infiltrates, B cells together with T cells and dendritic cells form organized nodular aggregates surrounded by neo-lymphatic vessels. The functional significance of these tertiary lymphoid organs remains to be fully defined. Intrarenal B cells may be part of a local system to enhance the immunological response by functioning as antigen presenting cells, and as a source for cytokines promoting T-cell proliferation and lymphatic neoangiogenesis. In this way, they could enhance the local immune response to persisting autoantigens in the tubulointerstitium.
Kidney International 04/2008; 73(5):533-7. · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Toll-like receptors (TLRs) exist on both myeloid and intrinsic renal cells contributing to the initiation of innate immunity during renal infection with uropathogenic Escherichia coli. Toll-interleukin 1 receptor (IL-1R) (TIR)8/SIGIRR is an orphan receptor of the TLR/IL-1R family, which suppresses TLR signaling of immune cells and is highly expressed in the kidney. Lack of TIR8/SIGIRR is associated with enhanced renal chemokine signaling upon exposure to lipopolysaccharide (LPS). This was because of TIR8/SIGIRR expression on resident intrarenal myeloid cells rather than tubular epithelial cells which express it on basolateral and luminal membranes. The lack of TIR8/SIGIRR does not enhance TLR/IL-1R signaling in tubular epithelial cells as was observed in monocytes. TIR8/SIGIRR is induced in monocytes treated with LPS or tumor necrosis factor and interferon-gamma in a dose-dependent manner but was downregulated in treated tubule epithelial cells. This cell type-specific regulation and function did not relate to mRNA splice variants but was associated with N- and O-glycosylation of the receptor in renal cells of myeloid and nonmyeloid origin. Our studies show that resident myeloid cells contribute to TLR-mediated antimicrobial immunity in the kidney and that this function is controlled by Tir8/sigirr. TIR8/SIGIRR does not suppress TLR signaling in tubular epithelial cells, which supports their role as sensors of microbial infection in the kidney.
Kidney International 08/2007; 72(2):182-92. · 8.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemokines are involved in the recruitment of leukocytes to vascularized allografts. CCR1 is a receptor for various proinflammatory chemokines and CCR1 blockade reduces renal allograft injury in rabbits. The purpose of the study was to characterize CCR1-positive cells in human renal allografts.
Formalin-fixed, paraffin-embedded allograft nephrectomies (n = 9) and non-involved parts of tumour nephrectomies (n = 10) were studied. Immunohistochemistry for CCR1, CD3 and CD68 was performed on consecutive sections. Double immunofluorescence for CCR1 and CD3, CD20, CD68, DC-SIGN and S100 was used on selected cases. Expression of CCR1 mRNA and the ligands CCL3 and CCL5 was studied in renal allograft biopsies with acute rejection (n = 10), with chronic allograft nephropathy (n = 8) and controls (n = 8).
CCR1 protein was expressed by circulating cells in glomerular and peritubular capillaries, colocalizing with CD68. In renal allografts CCR1-positive cells were present within glomerular tufts, but only scattered CCR1-positive cells were found in tubulointerstitial infiltrates. CCR1 did not colocalize with the majority of CD68-positive cells in the interstitium. The small number of CCR1-positive interstitial cells were identified as CD20- or DC-SIGN-positive by double immunofluorescence. CCR1 mRNA was significantly increased in renal biopsies with acute allograft rejection (P < 0.001), and with chronic allograft nephropathy (P < 0.05), it correlated with the expression of CCL3 and CCL5, and with serum-creatinine.
CCR1 mRNA expression was associated with renal function in allografts. CCR1 protein expression was restricted to monocytes, CD20-positive B cells and DC-SIGN-positive dendritic cells. Thus most interstitial macrophages were CCR1 negative, which may relate to down-regulation after migration into the interstitium in human renal allografts.
[Show abstract][Hide abstract] ABSTRACT: Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-1alpha mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions about rodent models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.
Journal of the American Society of Nephrology 07/2007; 18(6):1765-76. · 8.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To summarize the recent advances in the role of Toll-like receptors (TLRs) in innate immunity, with a special focus on recent studies addressing the expression and function of TLRs in kidney disease.
Pathogen-recognition receptors including TLRs mediate immune activation upon pathogen recognition in different extracellular and intracellular compartments. In contrast to professional antigen-presenting cells, renal cells express a limited pattern of TLR (i.e. express TLR1-TLR6 but lack expression of the endosomal TLR7-TLR9). TLRs on renal cells contribute to the innate immune response in renal infection. Furthermore, recent studies provide experimental evidence for the functional role of TLRs in immune complex disease and autoimmunity. Furthermore, the recognition of endogenous molecules released from injured cells such as biglycan or heat-shock proteins may contribute to acute tubular injury and seem to provide adjuvant activity for renal inflammation. Furthermore, TLR7 and TLR9 are involved in the pathogenesis of lupus nephritis.
The field of TLR research elucidates the molecular mechanisms of infection-associated kidney diseases but may also further support the concept that innate immunity significantly contributes to the so-called types of nonimmune kidney diseases.
Current Opinion in Nephrology and Hypertension 06/2007; 16(3):177-83. · 3.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemokines comprise a family of structurally related chemotactic proteins. They bind to about 20 corresponding receptors. Chemokines provide a general communication system for cells, and regulate lymphocyte migration under normal (homeostatic) and inflammatory conditions. Chemokines organize microenvironments in lymphoid tissue, lymphoid organogenesis, and participate in vascular and lymphatic angiogenesis. Expressed at the site of injury in the kidney, chemokines are involved in the recruitment of specific leukocyte subsets to particular renal compartments. Here we summarize recent data on chemokine biology with a focus on the role of chemokines in the recruitment of neutrophils (polymorphonuclear leukocytes), monocytes/macrophages, dendritic cells, T cells, including regulatory T cells, and B cells in renal inflammation.
Seminars in Nephrology 06/2007; 27(3):260-74. · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
American Journal Of Pathology 04/2007; 170(4):1267-76. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system.
American Journal Of Pathology 03/2007; 170(2):457-68. · 4.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recruitment of leukocytes is a characteristic feature of tissue injury in systemic lupus erythematosus, including lupus nephritis. Locally secreted chemokines and their receptors are important mediators of leukocyte recruitment to the specific sites of immune complex injury, and contribute to renal inflammatory disease in the initiation and progression phase. Therefore, chemokines and chemokine receptors represent potential therapeutic targets in lupus nephritis. In this review we summarize available experimental and human data supporting their functional role in lupus nephritis. Moreover, interventional studies with chemokine and chemokine receptor antagonists that show the therapeutic potential of chemokine antagonists in experimental models of lupus nephritis and potentially in human renal disease are discussed.
Seminars in Nephrology 02/2007; 27(1):81-97. · 2.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advances in the understanding of innate pathogen recognition revealed that nucleic acids have immunomodulatory functions in inflammation. A set of Toll-like pattern-recognition receptors recognize various types of microbial nucleic acids, i.e. double-stranded viral RNA (TLR3), single-stranded viral RNA (TLR7 and TLR8), and viral and bacterial CpG-DNA (TLR9). All of these TLRs are differentially expressed in the healthy and diseased kidney and TLR ligation was shown to initiate and modulate experimental glomerulonephritis. In this review we summarize the arising evidence in this field and discuss new hypotheses for the pathogenesis of kidney diseases that are triggered by infectious organisms.