title: Semicarbazide-sensitive amine oxidase (SSAO) inhibition ameliorates kidney fibrosis in a unilateral ureteral obstruction murine model.
abstract: Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme known for its dual function in mediating inflammation and reactive oxygen species production. However, the role of SSAO inhibitors in limiting kidney fibrosis is unclear. We aimed to determine the effectiveness of a SSAO inhibitor (SSAOi; PXS4728A) as an antifibrotic agent using a 7-day unilateral ureteric obstruction (UUO) model of acute kidney fibrosis in 6- to 8-wk-old mice. The experimental groups were 1) Sham operated; 2) UUO; 3) UUO+SSAOi (2 mg/kg); 4) UUO+telmisartan, an angiotensin receptor blocker (3 mg/kg); and 5) UUO+SSAOi+telmisartan. Kidney tissue was analyzed for histological evidence of tubulointerstitial fibrosis, nitrotyrosine staining, and mRNA expression of markers associated with fibrosis and inflammation. Kidney SSAO activity was determined by radiometric [(14)C]benzylamine methodology. Our results show that SSAOi effectively suppresses UUO-mediated SSAO activity. Extracellular matrix markers, namely, fibronectin, collagen IV protein, and nitrotyrosine staining, were lower in UUO+SSAOi mice compared with untreated UUO mice. This was consistent with the attenuated mRNA expression of collagen IV and fibronectin. SSAOi effectively inhibited transforming growth factor-β1 (TGF-β1) and monocyte chemoattractant protein-1 (MCP-1) expression to a similar extent to that observed with telmisartan. Individually, SSAOi and telmisartan induced a reduction in interstitial leukocyte and macrophage accumulation. However, the combination of SSAOi and telmisartan was more effective at reducing inflammatory cell infiltration. These results demonstrate that SSAO inhibition significantly suppresses profibrotic and proinflammatory cytokine secretion, reduces oxidative stress, and limits inflammatory cell accumulation and extracellular matrix expression in an acute model of renal fibrosis.
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia;
authors.forename: May
authors.initials: M
authors.lastname: Wong
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia;
authors.forename: Sonia
authors.initials: S
authors.lastname: Saad
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia;
authors.forename: Simon
authors.initials: S
authors.lastname: Gross
authors.affiliation: Pharmaxis, Limited, Frenchs Forest, Sydney, New South Wales, Australia; and.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jarolimek
authors.affiliation: Pharmaxis, Limited, Frenchs Forest, Sydney, New South Wales, Australia; and.
authors.forename: Heidi
authors.initials: H
authors.lastname: Schilter
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Chen
authors.affiliation: Department of Anatomical Pathology, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia; carol.pollock@sydney.edu.au.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Pollock
authors.affiliation: Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, Sydney, New South Wales, Australia;
authors.forename: Muh Geot
authors.initials: MG
authors.lastname: Wong
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005355:Fibrosis; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008810:Mice, Inbred C57BL; D012663:Semicarbazides / Q000494:pharmacology; D000077333:Telmisartan; D014517:Ureteral Obstruction / Q000473:pathology
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D004791:Enzyme Inhibitors; D012663:Semicarbazides; C010059:carbamylhydrazine; D006631:Amine Oxidase (Copper-Containing); D000077333:Telmisartan
keywords: anti-inflammatory; semicarbazide-sensitive amine oxidase; tubulointerstitial fibrosis; unilateral ureteral obstruction murine model