Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury

PLoS One. 2017 Feb 24;12(2):e0168981. doi: 10.1371/journal.pone.0168981. eCollection 2017.

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.

MeSH terms

  • Acute Kidney Injury / drug therapy*
  • Acute Kidney Injury / pathology
  • Animals
  • Disease Models, Animal
  • Hepatitis A Virus Cellular Receptor 1 / metabolism
  • Humans
  • Kidney / drug effects
  • Kidney / pathology
  • Kidney Tubular Necrosis, Acute / drug therapy*
  • Kidney Tubular Necrosis, Acute / physiopathology
  • Mice
  • Reperfusion Injury / drug therapy*
  • Reperfusion Injury / physiopathology
  • alpha 1-Antitrypsin / administration & dosage*
  • alpha 1-Antitrypsin / metabolism

Substances

  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin

Grant support

This study was supported by a grant from the Dutch Kidney Foundation (https://www.nierstichting.nl/). Project Code IP10.21 to LB Hilbrands. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.