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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.
Highlights
Renal ischemia-reperfusion (I/R) injury is a frequent cause of acute kidney injury (AKI) in a variety of clinical conditions such as cardiac or aortic surgery and kidney transplantation, and is associated with significant morbidity and mortality
Kidneys from human AAT (hAAT)-treated mice displayed less extensive tubular necrosis compared to the human serum albumin (hAlb)-treated control animals (Fig 2, panels E and F), with a significantly reduced histological damage score in the cortico-medullary junction and inner medulla at day 2 after kidney I/R injury (Fig 2G)
The current study shows that in vivo administration of clinical grade hAAT improves renal function, decreases acute tubular necrosis and ameliorates AKI following experimental kidney I/R damage
Summary
Renal ischemia-reperfusion (I/R) injury is a frequent cause of acute kidney injury (AKI) in a variety of clinical conditions such as cardiac or aortic surgery and kidney transplantation, and is associated with significant morbidity and mortality. Ischemic injury of the kidney causes the release of damage-associated molecular patterns (DAMPs) by impaired endothelial and tubular epithelial cells [1] These DAMPs are rapidly sensed by pattern recognition receptors, which together with the formation of reactive oxygen species after reperfusion lead to an inflammatory response. Its main physiological role is to inhibit the activity of different endogenous serine proteases, such as neutrophil-derived elastase and proteinase-3 [2,3,4]. These proteolytic enzymes contribute to the inflammatory response by activating pro-cytokines and through the formation of DAMPs. Due to its anti-protease activity, AAT can inhibit these pathways, exerting anti-inflammatory and tissue-protective effects. Its mechanism of action is not completely understood, and some studies suggest that the protective effects of AAT are independent of its serine protease inhibiting activity [11]
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