Abstract: FR-PO1228
Mechanisms of Cardiac Injury in Cardiovascular-Kidney-Metabolic (CKM) Syndrome: Inflammatory Signaling via miR-452-5p Downregulation of Cardiac NKIRAS1-NF-kB Signaling
Session Information
- CKD: Mechanisms, AKI, and Beyond - 2
November 07, 2025 | Location: Exhibit Hall, 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 System, Columbia, Missouri, United States
- Eirin, Alfonso, Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background
Cardiovascular-Kidney-Metabolic (CKM) syndrome entails complex pathophysiological interactions leading to multiorgan dysfunction and a high rate of renal and cardiovascular disease (CVD), largely driven by the development of heart failure (HF). Mechanisms leading to HF in CKM syndrome are unknown. Emerging research focuses on micro-RNAs (miRNAs) and their role in the pathophysiology of renal disease, CVD, and HF. However, whether they play a role in the development of cardiac injury in CKM syndrome has not been investigated.
Methods
We develop a novel swine model that recapitulates many features of CKM syndrome. CKM syndrome and normal pigs (n=4 each, 2 males/2 females) were studied for 14 weeks. Renal (multi-detector CT, histology) and cardiac morphology and function (echocardiography) were quantified in vivo. Unbiased cardiac miRNA-seq identified miR-452-5p as the most significantly upregulated miRNA in CKM syndrome and confirmed that it is primarily expressed in cardiomyocytes (FISH). We next searched for potential targets (Target Scan) and identified NKIRAS1, a critical regulator of NF-kB signaling, which PCR confirmed. In addition, another group of pigs with CKM syndrome (n=4, 2 males/2 females) were treated with a single intracoronary (IC) administration of anti-miR-452-5p, and effects on cardiac function and NKIRAS1 signaling were quantified 4 weeks later.
Results
The cardiac, renal, and metabolic phenotype of CKM syndrome pigs was accompanied by cardiac upregulation of miR-452-5p, decreased NKIRAS1, and increased NF-kB (Fig.1A-F). The effects of miR-452-5p on NKIRAS1-NF-kB were confirmed in vitro (pig cardiomyocytes with miR-452-5p overexpression, Fig.1G). Notably, IC anti-miR-452-5p therapy safely rescued NKIRAS1, decreased NF-kB, and improved cardiac function without off-target effects (Fig. 2).
Conclusion
Our study identifies a new target and mechanism for developing cardiac injury and HF in CKM syndrome. Furthermore, it supports the feasibility of a potential new therapeutic strategy via a targeted mechanistic intervention.
Funding
- NIDDK Support