Cardiac arrhythmias after renal I/R depend on IL-1β

J Mol Cell Cardiol. 2019 Jun:131:101-111. doi: 10.1016/j.yjmcc.2019.04.025. Epub 2019 Apr 25.

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-1β 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-1β, 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-1β 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-1β is produced after sensing renal injury through NRLP3-CASP1, and IL-1β 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.

Keywords: Arrhythmias; Cardiorenal syndrome; Electrophysiology; IL-1β; Innate immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / etiology*
  • Arrhythmias, Cardiac / metabolism*
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Immunity, Innate / physiology
  • Interleukin-1beta / metabolism*
  • Kidney Diseases / complications*
  • Kidney Diseases / immunology
  • Kidney Diseases / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Reperfusion Injury / complications*
  • Reperfusion Injury / immunology
  • Reperfusion Injury / metabolism*
  • Signal Transduction / physiology

Substances

  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Caspase 1