Delayed Chemokine Receptor 1 Blockade Prolongs Survival in Collagen 4A3–Deficient Mice with Alport Disease

Ninichuk, Volha; Groß, Oliver; Reichel, Christoph; Khandoga, Andrej; Pawar, Rahul D.; Ciubar, Raluca; Segerer, Stephan; Belemezova, Emilia; Radomska, Ewa; Luckow, Bruno; Lema, Guillermo Pérez de; Murphy, Philip M.; Gao, Ji-Liang; Henger, Anna; Kretzler, Matthias; Horuk, Richard; Weber, Manfred; Krombach, Fritz; Schlöndorff, Detlef; Anders, Hans‐Joachim

doi:10.1681/asn.2004100871

Cited by 95 publications

(86 citation statements)

References 26 publications

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“…These results are consistent with a Ccr1-dependent homing of leukocytes from the blood to the kidney. In line with this, in vitro and in vivo studies have reported a role for Ccr1 in T cell and mononuclear phagocyte adhesion and transendothelial migration (14,17,18,27,42,43). Thus, BL5923-induced inhibition of renal T cell and macrophage infiltration could be related to reduced Ccr1-mediated adhesion of leukocytes to activated peritubular capillaries.…”

Section: Discussionmentioning

confidence: 59%

“…The use of Ccr1-deficient mice or small-molecule Ccr1 antagonists efficiently reduced interstitial infiltration of T cells, mononuclear phagocytes, and/or neutrophils in different mouse models of nephropathy (13,14,17,18,23,27,28,43). In particular, s.c. injections of the Ccr1 antagonist BX471 in MRL-Fas(lpr) mice led to reduced numbers of macrophages, T cells, and Ki-67 positive proliferating cells and reduced fibrosis in the interstitium.…”

Section: Discussionmentioning

confidence: 99%

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CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Bignon

Gaudin

Hémon

et al. 2014

The Journal of Immunology

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Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4+ T cells, Ly6C+ monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 99%

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Bignon

Gaudin

Hémon

et al. 2014

The Journal of Immunology

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“…Nephrogenic T-cell response and T-cell infiltration in interstitial nephritis initiate, amplify, and perpetuate local inflammatory response which contributes to tubular atrophy and interstitial fibrosis. 34,[36][37][38] However, the emergence of tubular interstitial fibrosis in our a3/Rag-1 DKO mice, as suggested by Ninichuk et al, 32 could result from macrophage recruitment and activation via MCP-1 expression. [33][34][35] Lower serum creatinine levels in the double null mice indicate that ablating active lymphocytes decreases the injury to the renal interstitium.…”

Section: Lymphocytes and Tissue Fibrosis Vs Lebleu Et Almentioning

confidence: 98%

Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease

LeBleu

Sugimoto

Miller

et al. 2008

Laboratory Investigation

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One current theory for the emergence of glomerular nephritis implicates Th1-type cellular responses associated with delayed-type hypersensitivity, involving T cells and macrophages. Using a mouse model for progressive glomerulonephritis, we investigate the role of B and T cells in the pathogenesis of glomerular inflammation. Deletion of a3 chain of type IV collagen in mice (a3(IV) collagen null mice) results in GBM defects, glomerulonephritis and tubulointerstitial inflammation, fibrosis and significant immune infiltration including activated B-and T-lymphocytes. To evaluate the contribution of lymphocytes to the pathogenesis of glomerulonephritis and renal fibrosis, we generated mice that are deficient in both the a3(IV) collagen and Rag-1 (a3/Rag-1 DKO). Lymphocyte deficiency significantly reduces fibrosis in the renal interstitium, but ultrastructural GBM defects persist. Interestingly, glomerulonephritis in the double null mice persists at a similar level with comparable proteinuria. Here we demonstrate that despite the presence of B-cell and T-cells in the inflamed glomeruli, their deletion does not impede the emergence of glomerulonephritis but has a negative impact on the progression of renal interstitial fibrosis.

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“…39 Purity of isolated cells was verified by flow cytometry. Separated cells were labeled with PKH26 (red fluorescent cell linker kit; Sigma-Aldrich Chemicals, Steinheim, Germany) and labeling efficacy was assessed by flow cytometry.…”

Section: In Vivo Assay Of Renal Macrophage Recruitmentmentioning

confidence: 99%

Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36–3′PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice

Ninichuk¹,

Clauß²,

Kulkarni³

et al. 2008

The American Journal of Pathology

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125

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Diabetic kidney disease is associated with monocyte chemoattractant CC chemokine ligand 2 (CCL2)-dependent glomerular and interstitial macrophage recruitment. In addition, nephropathy is delayed in Ccl2 mutant diabetic mice. However, whether the late onset of therapeutic Ccl2 blockade modulates the progression of advanced diabetic nephropathy remains unknown. We addressed this question by antagonizing Ccl2 with mNOX-E36 -3PEG, an anti-Ccl2 L-enantiomeric RNA aptamer (ie, a Spiegelmer), which binds murine Ccl2 and blocks the recruitment of ex vivo-labeled macrophages to the kidneys of db/db mice with type 2 diabetes. We injected mNOX-E36 -3PEG subcutaneously at a dose of 50 mg/kg three times per week into uninephrectomized (1K) db/db mice with advanced glomerulopathy from 4 to 6 months of age. mNOX-E36 -3PEG reduced the number of glomerular macrophages by 40% compared with nonfunctional (control) Spiegelmertreated 1K db/db mice. This result was associated with protection from diffuse glomerulosclerosis and significantly improved the glomerular filtration rate. mNOX-E36 -3PEG also reduced renal Ccl2 mRNA and protein expression compared with control Spiegelmer-treated 1K db/db mice of the same age. Together, the late onset of therapeutic Ccl2 blockade, eg, with specific Spiegelmers, offers protection from diffuse glomerulosclerosis in type 2 diabetic db/db mice and, thus, may represent a novel therapeutic strategy for advanced glomerulosclerosis.

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Delayed Chemokine Receptor 1 Blockade Prolongs Survival in Collagen 4A3–Deficient Mice with Alport Disease

Cited by 95 publications

References 26 publications

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease

Late Onset of Ccl2 Blockade with the Spiegelmer mNOX-E36–3′PEG Prevents Glomerulosclerosis and Improves Glomerular Filtration Rate in db/db Mice

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