Role of NLRP3 inflammasome in cardiac damage in the setting of an acute cardiorenal syndrome

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): ISCIII, Ministerio de Universidades, Education and Research Council of Madrid, Biomedicine Network Comunidad de Madrid Background Acute kidney injury (AKI) is usually associated with an acute cardiac impairment known as cardiorenal syndrome type 3 (CRS3). AKI induces the activation of the immune system being the connection with the disturbance in remote organs as the heart. In response to tissue damage, different inflammatory pathways are activated. In this sense, activation of cardiac nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome has been studied in several cardiac pathologies. Nevertheless, the role of cardiac NLRP3 in ventricular cardiomyocytes as a consequence of renal damage is unknown. Purpose The overall aim of this study was to analyse the involvement of NLRP3 in AKI-induced cardiac damage in CRS3. Firstly, we evaluated the predictive value for mortality of the inflammatory component associated with the NLRP3 in a cohort of AKI patients. Then, we studied whether cardiac NLRP3 activation takes place after AKI induction and whether this may be associated with functional alterations in ventricular cardiomyocytes related to cardiac dysfunction and predisposition to ventricular arrhytmia. Methods We have studied cardiac alterations resulting from AKI induced by folic acid (FA, 250 mg/Kg) after 72 hours in wild-type (WT), Nlrp3-/- and WT AKI mice treated with the NLRP3 inhibitor MCC950 (10 mg/Kg). We examined plasma, renal and cardiac inflammatory components associated with NLRP3, as well as cardiomyocyte intracellular Ca2+ handling by confocal microscopy in all experimental groups. In AKI patients, we analysed systemic NLRP3-related cytokine levels and their possible relationship with markers of renal and cardiac damage and the prediction of mortality. Results FA-induced AKI caused a worsening of contractile function in WT cardiomyocytes due to decreased systolic Ca2+ release after 72 hours. It was accompanied by impaired Ca2+ reuptake via SERCA2a. Nevertheless, in both MCC950-treated and NLRP3-/- mice, these alterations were significantly prevented. During diastole, significant Ca2+ leakage from the sarcoplasmic reticulum was observed after 72 hours of AKI-induction, as well as increased pro-arrhythmogenic events. These alterations were prevented in both NLRP3-/- and MCC950-treated AKI mice. In AKI patients, we found that NLRP3-related cytokines increased from the time of admission to 72 hours, significantly associated with biomarkers of renal and cardiovascular damage, and exhibited a high potential to predict mortality. Conclusions AKI impairs the cytosolic Ca2+ handling in ventricular cardiomyocytes that are translated into contractile dysfunction and increased occurrence of pro-arrhythmogenic events. These cardiac alterations are strongly prevented under NLRP3 blockade, demonstrating the deleterious role of its cardiac activation in CRS3. In addition, results from AKI patients point to NLRP3 as relevant prognostic target in AKI patients at the time of admission to hospital.