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Volume 81, Issue 2, Pages (January 2012)

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1 Volume 81, Issue 2, Pages 170-178 (January 2012)
Mice with defective Fas ligand are protected from crescentic glomerulonephritis  Ruth M. Tarzi, Phoebe E.H. Sharp, John P. McDaid, Liliane Fossati-Jimack, Paul E. Herbert, Charles D. Pusey, H. Terence Cook, Anthony N. Warrens  Kidney International  Volume 81, Issue 2, Pages (January 2012) DOI: /ki Copyright © 2012 International Society of Nephrology Terms and Conditions

2 Figure 1 Functional and histological parameters at Day 15 after induction of nephrotoxic nephritis (NTN) in wild-type (WT) and generalized lymphoproliferative disorder (GLD) mice. (a) Glomerular thrombosis score, (b) percentage glomerular crescents, (c) urinary albumin/creatinine ratio (mg/mmol), (d) serum albumin (g/l), (e) serum urea (mmol/l), (f) apoptotic bodies/gcs. Dashed lines represent values for a group of normal WT mice. gcs, glomerular cross-section. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

3 Figure 2 Histology at Day 15 after induction of nephrotoxic nephritis (NTN). (a) Periodic acid-Schiff-stained wild-type (WT) kidney section showing glomerular hypercellularity, and a glomerular crescent; (b) generalized lymphoproliferative disorder (GLD) kidney at Day 15 after induction of NTN showing mild glomerular hypercellularity only. (c, e) Immunoperoxidase staining for CD68 in WT kidney showing interstitial and glomerular macrophage infiltration. (d, f) Immunoperoxidase staining for CD68 in GLD kidney showing glomerular, but little interstitial, macrophage infiltration. Apoptotic bodies were present in WT glomeruli (g) but absent from GLD glomeruli by TUNEL staining (h). Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

4 Figure 3 Day 15 after induction of NTN. (a) CD68-positive macrophages/glomerular cross-section (gcs); (b) CD68-positive macrophage interstitial infiltration assessed by image analysis; (c) relative expression of MCP-1 mRNA in GLD and WT mice post nephrotoxic nephritis (NTN) compared with control wild-type (WT) and generalized lymphoproliferative disorder (GLD) mice; (d) neutrophils/gcs 24h after induction of NTN. Dashed lines represent values for a group of normal WT mice. MCP, monocyte chemoattractive protein; ns, not significant. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

5 Figure 4 Deposited and circulating immunoglobulin (Ig)G responses in WT and GLD mice after the induction of nephrotoxic nephritis (NTN). (a) Quantification of deposited glomerular mouse IgG at Day 1, Day 8, and Day 15 after induction of NTN (minimum n=7/group). (b) Enzyme-linked immunosorbent assay (ELISA) for serum total sheep IgG (1:1000 dilution) at Day 1, Day 8, and Day 15 after induction of nephrotoxic serum. AFU, arbitrary fluorescence units; GLD, generalized lymphoproliferative disorder; NS, not significant; WT, wild type. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

6 Figure 5 Splenocyte 3H thymidine incorporation at 72h after exposure to 100mcg/ml sheep IgG (left panels), and cytokine release into supernatant (right hand panel) after exposure to sheep IgG in vitro. (a) Splenocytes collected 7 days after immunization alone, without injection of nephrotoxic serum; (b) splenocytes collected at 10 days after induction of nephrotoxic nephritis with preimmunization and nephrotoxic serum. c.p.m., counts per minute; GLD, generalized lymphoproliferative disorder; IgG, immunoglobulin G; IFN, interferon; IL, interleukin; NS, not significant; NTN, nephrotoxic nephritis; WT, wild type. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

7 Figure 6 Intrarenal T-cell infiltration and intrarenal cytokine mRNA at Day 15 after induction of nephrotoxic nephritis. (a) CD4-positive T cells/gcs; (b) relative expression of IFN-γ mRNA between wild-type (WT) and, generalized lymphoproliferative disorder (GLD) mice at Day 15 post nephrotoxic nephritis (NTN); (c) relative expression of interleukin (IL)-4 mRNA; (d) relative expression of IL-12p40 mRNA. WT and GLD controls refer to unmanipulated age-matched control mice. gcs, glomerular cross-section; NS, not significant. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

8 Figure 7 Nephrotoxic nephritis in bone marrow-transplanted mice at Day 8 after induction of NTN. (a) Glomerular thrombosis score; (b) percentage glomerular crescents; (c) serum urea (mmol/l); (d) urinary albumin/creatinine ratio (mg/mmol); (e) Enzyme-linked immunosorbent assay (ELISA) for serum anti-sheep immunoglobulin (Ig)G; (f) apoptotic bodies/glomerular cross-section. Dashed lines refer to normal values for a group of control wild-type (WT) mice. gcs, glomerular cross-section; NTN, nephrotoxic nephritis; OD, optical density. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions

9 Figure 8 Expression of Fas ligand (FasL) in the kidney and analysis of functional effects of generalized lymphoproliferative disorder (GLD) mutation in mesangial cells. (a) Relative expression of FasL mRNA in whole kidney in unmanipulated wild-type (WT) mice (WT control) and WT mice at Day 15 after the induction of nephrotoxic nephritis (NTN) (WT NTN). (b) Flow cytometry for FasL on cultured mesangial cells. Dotted line: fluorescein isothiocyanate (FITC)-conjugated antihuman immunoglobulin (Ig)G secondary antibody only; black line, recombinant FasFc protein ((Fas conjugated to human Fc) plus secondary antibody). (c) Monocyte chemoattractive protein (MCP)-1 measured in supernatant of serum-starved mesangial cells unstimulated, or stimulated with 10ng/ml interleukin (IL)-1 (representative results from five separate experiments). (d) MCP-1 levels measured in supernatants of serum-starved mesangial cells unstimulated, or stimulated with 10ng/ml tumor necrosis factor (TNF)-α (representative of three separate experiments). ns, not significant. Kidney International  , DOI: ( /ki ) Copyright © 2012 International Society of Nephrology Terms and Conditions


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