Abstract: FR-PO999
CKD, Heart Failure, Cytokines, and NF-κB: Is There a Connection?
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Chade, Alejandro R., University of Missouri, Columbia, Missouri, United States
- Mohamed, Tamer, University of Louisville, Louisville, Kentucky, United States
- Eirin, Alfonso, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States
Background
Nuclear factor kappa (NF-κB) is a master transcription factor of inflammatory signaling and its prolonged activation is cytotoxic and may promote heart failure (HF). We developed a translational swine model of chronic kidney disease (CKD) that displays early-stage HF and cardiac activation of NF-κB. However, the mechanisms underpinning cardiac NF-kB activation in CKD remain unclear. We hypothesize that inflammatory cytokines released from the kidney and retained in the heart contribute to cardiac NF-κB activation and cardiac injury in CKD.
Methods
Normal and CKD pigs (n=6 each) were studied after 14 weeks; their systemic inflammatory cytokine profile was characterized (pig Luminex multi-panel assay) and their renal (renal vein - systemic) and cardiac (coronary sinus - systemic) gradients calculated. In vitro NF-kB expression (qPCR) and activation (immunofluorescence) was studied in pig heart slices and cardiomyocytes exposed to normal plasma, and CKD plasma with or without cytokine neutralizing antibodies (NA).
Results
Out of 13 cytokines, we found that tumor necrosis factor (TNF)-α and interleukin (IL)-6 showed the most significant increase in CKD, paired with positive renal and negative cardiac gradients, suggesting TNF-α/IL-6 renal release and cardiac retention. In vitro NF-kB expression and activation were higher in heart slices and cardiomyocytes exposed to CKD plasma but decreased in those treated with TNF-α and IL-6 NA (Figure).
Conclusion
These observations shed light into targeted mechanisms of cardiac NF-kB activation and may support future development of novel modulatory strategies to offset cardiac injury in CKD.
Funding
- NIDDK Support