Abstract
BackgroundLonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capacities. In the present study, we aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairmentMethodology/Principal findingsAddition of L. obliqua venom to purified prekallikrein and human plasma in vitro or to vascular smooth muscle cells (VSMC) in culture, was able to generate kallikrein in a dose-dependent manner. Injected in rats, the venom induced AKI and increased kallikrein levels in plasma and kidney. Kallikrein inhibition by aprotinin prevented glomerular injury and the decrease in glomerular filtration rate, restoring fluid and electrolyte homeostasis. The mechanism underlying these effects was associated to lowering renal inflammation, with decrease in pro-inflammatory cytokines and matrix metalloproteinase expression, reduced tubular degeneration, and protection against oxidative stress. Supporting the key role of kallikrein, we demonstrated that aprotinin inhibited effects directly associated with vascular injury, such as the generation of intracellular reactive oxygen species (ROS) and migration of VSMC induced by L. obliqua venom or by diluted plasma obtained from envenomed rats. In addition, kallikrein inhibition also ameliorated venom-induced blood incoagulability and decreased kidney tissue factor expressionConclusions/SignificanceThese data indicated that kallikrein and consequently kinin release have a key role in kidney injury and vascular remodeling. Thus, blocking kallikrein may be a therapeutic alternative to control the progression of venom-induced AKI and vascular disturbances.
Highlights
IntroductionThe clinical profile evolves to acute kidney injury (AKI), which is the main cause of death following this type of envenomation [3,4,5]
Envenomation resulting from contact with Lonomia obliqua caterpillars has been recognized as a neglected public health issue that mainly occurs in impoverished communities in the rural areas of the southern regions of Brazil
In regions of southern and southeast Brazil, accidents with the venomous caterpillar Lonomia obliqua have been an emergent problem, for their high incidence rates, and by the severity of the clinical consequences observed in envenomation cases
Summary
The clinical profile evolves to acute kidney injury (AKI), which is the main cause of death following this type of envenomation [3,4,5]. In addition to the direct cytotoxic effects of venom toxins, renal hypoperfusion appears to be an important underlying mechanism, because signs of glomerular fibrin deposition and hemodynamic instability (systemic hypotension and increased renal vascular permeability) have been detected in rats injected with L. Role of kallikrein in Lonomia obliqua venom-induced acute kidney injury obliqua venom [6]. Lonomia obliqua venom is nephrotoxic and acute kidney injury (AKI) is the main cause of death among envenomed victims. Mechanism underlying L. obliqua-induced AKI involves renal hypoperfusion, inflammation, tubular necrosis and loss of glomerular filtration and tubular reabsorption capacities. We aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairment
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