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1.
J Mol Cell Cardiol ; 131: 101-111, 2019 06.
Article in English | MEDLINE | ID: mdl-31029578

ABSTRACT

AIMS: Cardiac arrhythmias are one of the most important remote complications after kidney injury. Renal ischemia reperfusion (I/R) is a major cause of acute renal injury predisposing to several remote dysfunctions, including cardiac electrical disturbance. Since IL-1ß production dependent on NLRP3 represents a link between tissue malfunctioning and cardiac arrhythmias, here we tested the hypothesis that longer ventricular repolarization and arrhythmias after renal I/R depend on this innate immunity sensor. METHODS AND RESULTS: Nlrp3-/- and Casp1-/- mice reacted to renal I/R with no increase in plasma IL-1ß, different from WT (wild-type) I/R. A prolonged QJ interval and an increased susceptibility to ventricular arrhythmias were found after I/R compared to Sham controls in wild-type mice at 15 days post-perfusion, but not in Nlrp3-/- or CASP1-/- I/R, indicating that the absence of NLRP3 or CASP1 totally prevented longer QJ interval after renal I/R. In contrast with WT mice, we found no renal atrophy and no renal dysfunction in Nlrp3-/- and Casp1-/- mice after renal I/R. Depletion of macrophages in vivo after I/R and a day before IL-1ß peak (at 7 days post-perfusion) totally prevented prolongation of QJ interval, suggesting that macrophages might participate as sensors of tissue injury. Moreover, treatment of I/R-WT mice with IL-1r antagonist (IL-1ra) from 8 to 15 days post perfusion did not interfere with renal function, but reversed QJ prolongation, prevented the increase in susceptibility to ventricular arrhythmias and rescued a close to normal duration and amplitude of calcium transient. CONCLUSION: Taken together, these results corroborate the hypothesis that IL-1ß is produced after sensing renal injury through NRLP3-CASP1, and IL-1ß on its turn triggers longer ventricular repolarization and increase susceptibility to cardiac arrhythmias. Still, they offer a therapeutic approach to treat cardiac arrhythmias that arise after renal I/R.


Subject(s)
Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/metabolism , Interleukin-1beta/metabolism , Kidney Diseases/complications , Kidney Diseases/metabolism , Reperfusion Injury/complications , Reperfusion Injury/metabolism , Animals , Caspase 1/genetics , Caspase 1/metabolism , Immunity, Innate/physiology , Kidney Diseases/immunology , Male , Mice , Mice, Inbred C57BL , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Reperfusion Injury/immunology , Signal Transduction/physiology
2.
J Biol Chem ; 289(20): 13701-5, 2014 May 16.
Article in English | MEDLINE | ID: mdl-24692555

ABSTRACT

The inflammatory cytokine IL-1ß is critical for host responses against many human pathogens. Here, we define Group B Streptococcus (GBS)-mediated activation of the Nod-like receptor-P3 (NLRP3) inflammasome in macrophages. NLRP3 activation requires GBS expression of the cytolytic toxin, ß-hemolysin, lysosomal acidification, and leakage. These processes allow the interaction of GBS RNA with cytosolic NLRP3. The present study supports a model in which GBS RNA, along with lysosomal components including cathepsins, leaks out of lysosomes and interacts with NLRP3 to induce IL-1ß production.


Subject(s)
Bacterial Proteins/metabolism , Carrier Proteins/metabolism , Hemolysin Proteins/metabolism , Inflammasomes/metabolism , Interleukin-1beta/biosynthesis , Macrophages/metabolism , RNA, Bacterial/metabolism , Streptococcus agalactiae/physiology , Animals , Humans , Interleukin-1beta/metabolism , Lysosomes/metabolism , Lysosomes/microbiology , Macrophages/cytology , Macrophages/microbiology , Mice , NLR Family, Pyrin Domain-Containing 3 Protein , Phagosomes/metabolism , Phagosomes/microbiology , Streptococcus agalactiae/metabolism
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