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Abstract: TH-PO097

IL33 Mediates Cardiomyopathy After AKI by Directly Signaling to Myocytes

Session Information

  • AKI: Mechanisms - I
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Florens, Nans, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • York, Allen J., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Molkentin, Jeffery D., Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

Group or Team Name

  • Heart Institute - Molecular Cardiovascular Biology

Acute kidney injury (AKI) is a major cardiovascular risk factor. However, few direct molecular mechanisms have been identified that show how AKI leads to cardiac disease. The aims of this project are to assess the role of IL33 in cardiac damage after AKI.


AKI was induced in mice by ischemia-reperfusion injury of both kidneys by 30 min of reversible artery occlusion in WT, IL33 null and mice in which the IL33-receptor was deleted in cardiomyocytes. We also generated AAV9 carrying the IL33 cDNA (AAV-IL33) or an empty vector (AAV-EV) under a CMV promoter and injected 1012 viral particles intrathoracically in 6 to 9 days-old pups. Mice containing an insertion of a MerCreMer cDNA driven by the alpha-MHC (αMHCMCM, cardiomyocyte specific) promoter were crossed with a Il1rl1-loxP(fl)-targeted mouse (Il1rl1fl/fl, IL33-receptor) and recombination was obtained by intraperitoneal tamoxifen injections. Echocardiography was performed at 28 days after AKI surgery. Hearts were analyzed for fibrosis, cardiomyocyte area measurement, capillary content and myocardial ischemia with 2-nitroimidazole (EF5).


AKI induced cardiac dysfunction after 28 days, measured with echocardiography (mean ejection fraction (EF): 58 in shams and 46% with AKI, p<0.05). We observed increased fibrosis area in hearts from WT mice after AKI compared to Sham (2.3 vs 4.5% area, p<0.05) and increased cardiomyocyte surface areas indicative of hypertrophy (333 vs 597 µm2, p<0.05). Compared to Sham, WT AKI mice exhibited a capillary rarefaction (CD31 staining) along with increased myocardial EF5 staining, suggesting ongoing ischemia. However, cardiac function and architecture were preserved after 28 days of AKI in IL33 null mice. Moreover, WT mice injected with AAV9-IL33 showed impaired cardiac function compared to AAV9-EV injected ones after 8 weeks (EF 58 vs 42%, p<0.05). After AKI, targeted deletion of the IL33-receptor gene in cardiomyocytes (αMHCMCM Il1rl1fl/fl mice), preserved cardiac function and architecture with no significant increase in fibrosis, hypertrophy and no significant capillary rarefaction compared to Sham-operated mice (αMHCMCM only mice).


Secreted during AKI, IL33 has a direct toxic effect on the heart. Our observations are in contrast to some previous reports in the literature where IL33 was suggested to function as a cardioprotective factor.