title: Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition.
abstract: Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Katagiri
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Hamasaki
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.forename: Kousuke
authors.initials: K
authors.lastname: Negishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugaya
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.forename: Eisei
authors.initials: E
authors.lastname: Noiri
mesh_terms: D000199:Actins / Q000378:metabolism; D058186:Acute Kidney Injury / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D000499:Allylamine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000378:metabolism; D002945:Cisplatin / Q000009:adverse effects*; D004353:Drug Evaluation, Preclinical; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005355:Fibrosis; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D001549:Benzamides; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C493319:FABP1 protein, human; D050556:Fatty Acid-Binding Proteins; D015850:Interleukin-6; C000606296:PXS-4728A; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C544013:alpha-smooth muscle actin, mouse; C577686:interleukin-6, mouse; D000499:Allylamine; D006631:Amine Oxidase (Copper-Containing); D002945:Cisplatin