Renal and vascular effects of kallikrein inhibition in a model of Lonomia obliqua venom-induced acute kidney injury

Abstract

Background 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. In the present study, we aimed to investigate the contribution of kallikrein to the hemodynamic instability, inflammation and consequent renal and vascular impairment Methodology/Principal findings Addition 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 expression Conclusions/Significance These 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.

Caterpillar Venom: A Health Hazard of the 21st Century

“…Additionally, it was observed that L. obliqua venom induces the production of several cytokines, increased the expression of matrix metalloproteinases (MMPs) and increased the levels of nitric oxide (NO). As a consequence, these alterations resulted in tubular lesions and hereby the role of the activation of kininogen-kallikrein-BK-B1R/B2R in L. obliqua envenomation was shown [50]. Moreover, this work pointed out that cytokines and coagulation factors are produced in the plasma during the envenomation.…”

“…Firstly, they discovered that bradykinin, released from LMWK (directly) and HMWK (indirectly), as described previously in the section Contact Dermatitis with Edema and Erythema, contributes to kidney injury mainly by the activation of its two receptors, B1R and B2R [50]. Both receptors belong to the G-protein-coupled receptor group.…”

“…In some cases, this can lead to the development of an acute kidney injury (AKI). The venom-induced AKI cascade in the figure is copied with permission from [50].…”

“…The development of an acute kidney injury (AKI) is associated with a high morbidity and mortality. Envenomed patients experience a sudden loss of basic renal function, such as filtration and excretion capacities and the maintenance of homeostasis [15,50,85]. Berger et al (2019) [50] were the first to expose the mechanisms associated with the pathogenesis of renal damage by L. obliqua.…”

“…Moreover, this work pointed out that cytokines and coagulation factors are produced in the plasma during the envenomation. Also, activation of vascular smooth muscle cell (VSMC) procoagulant activity, increased reactive oxygen species production (ROS), and cell proliferation and migration were observed [50].…”