title: Pyridoxamine reduces postinjury fibrosis and improves functional recovery after acute kidney injury.
abstract: Acute kidney injury (AKI) is a common and independent risk factor for death and chronic kidney disease (CKD). Despite promising preclinical data, there is no evidence that antioxidants reduce the severity of injury, increase recovery, or prevent CKD in patients with AKI. Pyridoxamine (PM) is a structural analog of vitamin B6 that interferes with oxidative macromolecular damage via a number of different mechanisms and is in a phase 3 clinical efficacy trial to delay CKD progression in patients with diabetic kidney disease. Because oxidative stress is implicated as one of the main drivers of renal injury after AKI, the ability of PM to interfere with multiple aspects of oxidative damage may be favorable for AKI treatment. In these studies we therefore evaluated PM treatment in a mouse model of AKI. Pretreatment with PM caused a dose-dependent reduction in acute tubular injury, long-term postinjury fibrosis, as well as improved functional recovery after ischemia-reperfusion AKI (IR-AKI). This was associated with a dose-dependent reduction in the oxidative stress marker isofuran-to-F2-isoprostane ratio, indicating that PM reduces renal oxidative damage post-AKI. PM also reduced postinjury fibrosis when administered 24 h after the initiating injury, but this was not associated with improvement in functional recovery after IR-AKI. This is the first report showing that treatment with PM reduces short- and long-term injury, fibrosis, and renal functional recovery after IR-AKI. These preclinical findings suggest that PM, which has a favorable clinical safety profile, holds therapeutic promise for AKI and, most importantly, for prevention of adverse long-term outcomes after AKI.
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Nataliya I
authors.initials: NI
authors.lastname: Skrypnyk
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Paul
authors.initials: P
authors.lastname: Voziyan
authors.affiliation: Division of Pathology, Microbiology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Haichun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Christian R
authors.initials: CR
authors.lastname: de Caestecker
authors.affiliation: inVentiv Health Center, Montreal, Quebec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Theberge
authors.affiliation: inVentiv Health Center, Montreal, Quebec, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Drouin
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Biochemistry, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Billy
authors.initials: B
authors.lastname: Hudson
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee;
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Harris
authors.affiliation: Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Cell and Developmental Biology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; and mark.de.caestecker@vanderbilt.edu.
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D028421:Isoprostanes / Q000378:metabolism; D007684:Kidney Tubules / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D011733:Pyridoxamine / Q000097:blood / Q000627:therapeutic use*; D020127:Recovery of Function; D014803:Vitamin B Complex / Q000097:blood / Q000627:therapeutic use*
chemical_list: D028421:Isoprostanes; D014803:Vitamin B Complex; D011733:Pyridoxamine
keywords: oxidative stress; renal fibrosis; renal function