title: Interleukin-18 binding protein therapy is protective in adriamycin nephropathy.
abstract: Adriamycin nephropathy (AN) is an experimental model of focal segmental glomerulosclerosis (FSGS) in which macrophages are considered to play a pathogenic role. We hypothesize that interleukin-18 (IL-18), largely derived from macrophages, is a key contributor to kidney injury in AN and a potential therapeutic target. In this study, BALB/c mice received adriamycin (9.6 mg/kg) via tail vein injection and subsequently were treated with either neutralizing IL-18 binding protein (IL-18BP; 250 μg) or normal saline (control). At 5 wk, IL-18 was upregulated in AN, and IL-18BP therapy afforded significant protection against the development of AN, resulting in less proteinuria (P < 0.01), kidney dysfunction (P < 0.01), glomerulosclerosis (P < 0.001), and interstitial accumulation of macrophages and T cells (P < 0.001). Gene expression of IL-18 downstream inflammatory molecules, including inducible nitric oxide synthase (P < 0.001), TNF-α (P < 0.001), and IFN-γ (P < 0.01); IL-17 (P < 0.001) and the chemokines CCL2 (P < 0.01) and CCL5 (P < 0.005), was reduced. We demonstrate that IL-18 plays a significant role in the pathogenesis of AN. The protective effect of IL-18BP therapy illustrates the importance of immune mediators in chronic proteinuric kidney disease and highlights the potential of IL-18BP therapy.
authors.affiliation: Collaborative Transplant Research Group, Royal Prince Alfred Hospital, University of Sydney, Sydney, New South Wales, Australia. kate.wyburn@sydney.edu.au
authors.forename: Kate R
authors.initials: KR
authors.lastname: Wyburn
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chadban
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy; D036341:Intercellular Signaling Peptides and Proteins / Q000627:therapeutic use*; D020382:Interleukin-18 / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein; D004317:Doxorubicin