title: Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury.
abstract: Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Nuria
authors.initials: N
authors.lastname: Maicas
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: van der Vlag
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Janin
authors.initials: J
authors.lastname: Bublitz
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marinka
authors.initials: M
authors.lastname: Bakker-van Bebber
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Medicine, University of Colorado Health Sciences Center Denver, Colorado, United States of America.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands.
authors.forename: Vivienne
authors.initials: V
authors.lastname: Verweij
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.
authors.forename: Roos
authors.initials: R
authors.lastname: Masereeuw
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: Department of Nephrology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Luuk B
authors.identifier: http://orcid.org/0000-0002-4935-9765
authors.initials: LB
authors.lastname: Hilbrands
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007683:Kidney Tubular Necrosis, Acute / Q000188:drug therapy* / Q000503:physiopathology; D051379:Mice; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D000515:alpha 1-Antitrypsin / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin