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Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat.
Lab Invest. 2009 Apr; 89(4):470-84.LI

Abstract

Macrophages induce acute renal injury in anti-glomerular basement membrane (GBM) glomerulonephritis. This operates, in part, via activation of the c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt disease progression, including crescent formation, in a model of severe crescentic anti-GBM glomerulonephritis. WKY rats were immunized with sheep IgG and then injected with sheep anti-GBM serum (day 0). Animals were treated with the JNK inhibitor, CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe glomerulonephritis at day 24 with renal impairment and worsening proteinuria. These animals had severe glomerular lesions, with 60% of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in mRNA levels of TNF-alpha, iNOS, MMP-12, and TGF-beta1. In contrast, CC-401 treatment prevented renal impairment, suppressed proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response. CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (interleukin-10 and heme oxygenase-1). In addition, IL-1 induced MMP-12 and IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial protection against the progression of crescentic anti-GBM glomerulonephritis, which may be, in part, due to inhibition of the macrophage proinflammatory response.

Authors+Show Affiliations

Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Victoria, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19188913

Citation

Ma, Frank Y., et al. "Blockade of the c-Jun Amino Terminal Kinase Prevents Crescent Formation and Halts Established anti-GBM Glomerulonephritis in the Rat." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 89, no. 4, 2009, pp. 470-84.
Ma FY, Flanc RS, Tesch GH, et al. Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Lab Invest. 2009;89(4):470-84.
Ma, F. Y., Flanc, R. S., Tesch, G. H., Bennett, B. L., Friedman, G. C., & Nikolic-Paterson, D. J. (2009). Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. Laboratory Investigation; a Journal of Technical Methods and Pathology, 89(4), 470-84. https://doi.org/10.1038/labinvest.2009.2
Ma FY, et al. Blockade of the c-Jun Amino Terminal Kinase Prevents Crescent Formation and Halts Established anti-GBM Glomerulonephritis in the Rat. Lab Invest. 2009;89(4):470-84. PubMed PMID: 19188913.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Blockade of the c-Jun amino terminal kinase prevents crescent formation and halts established anti-GBM glomerulonephritis in the rat. AU - Ma,Frank Y, AU - Flanc,Robert S, AU - Tesch,Greg H, AU - Bennett,Brydon L, AU - Friedman,Glenn C, AU - Nikolic-Paterson,David J, Y1 - 2009/02/02/ PY - 2009/2/4/entrez PY - 2009/2/4/pubmed PY - 2009/5/16/medline SP - 470 EP - 84 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab. Invest. VL - 89 IS - 4 N2 - Macrophages induce acute renal injury in anti-glomerular basement membrane (GBM) glomerulonephritis. This operates, in part, via activation of the c-Jun amino terminal kinase (JNK) signaling pathway. However, it is unknown whether inhibition of JNK signaling is effective once the proinflammatory response is established in the injured kidney. This study examined whether blockade of JNK signaling could halt disease progression, including crescent formation, in a model of severe crescentic anti-GBM glomerulonephritis. WKY rats were immunized with sheep IgG and then injected with sheep anti-GBM serum (day 0). Animals were treated with the JNK inhibitor, CC-401, vehicle alone, or no treatment from day 7 until being killed on day 24 of disease. Untreated animals at day 7 showed significant proteinuria, focal glomerular lesions, marked glomerular macrophage and T-cell accumulation, and upregulation of proinflammatory mediators (TNF-alpha, iNOS, MMP-12). Untreated and vehicle-treated groups displayed severe glomerulonephritis at day 24 with renal impairment and worsening proteinuria. These animals had severe glomerular lesions, with 60% of glomeruli exhibiting fibrocellular crescents, in association with increased macrophage and T-cell accumulation (including macrophage giant cells) and a further increase in mRNA levels of TNF-alpha, iNOS, MMP-12, and TGF-beta1. In contrast, CC-401 treatment prevented renal impairment, suppressed proteinuria, and prevented severe glomerular and tubulointerstitial lesions, including crescent formation and granulomatous-like lesions. These protective effects were independent of glomerular macrophage and T-cell accumulation, and of the humoral immune response. CC-401 treatment inhibited expression of both pro- and antiinflammatory molecules (interleukin-10 and heme oxygenase-1). In addition, IL-1 induced MMP-12 and IL-10 production by cultured macrophages was found to be JNK dependent. In conclusion, blockade of JNK signaling provides substantial protection against the progression of crescentic anti-GBM glomerulonephritis, which may be, in part, due to inhibition of the macrophage proinflammatory response. SN - 1530-0307 UR - https://www.unboundmedicine.com/medline/citation/19188913/Blockade_of_the_c_Jun_amino_terminal_kinase_prevents_crescent_formation_and_halts_established_anti_GBM_glomerulonephritis_in_the_rat_ L2 - http://dx.doi.org/10.1038/labinvest.2009.2 DB - PRIME DP - Unbound Medicine ER -