Micro-RNA-532-3p: a potential target in CKD-HFpEF pathophysiology

Abstract

Background: Chronic kidney disease (CKD), an independent risk factor for heart failure with preserved ejection fraction (HFpEF), is present in over 50% of CKD patients and accounts for over 50% of hospital admissions for HF. We showed in a novel swine model of CKD-HFpEF that cardiac abnormalities associate with upregulation of pro-inflammatory nuclear factor kappa B (NF-kB). NF-κB activation is controlled by its natural inhibitor IkBα, a protein encoded by the NFKBIA gene that prevents its nuclear translocation, but the exact mechanisms remain unknown. We hypothesize that micro-RNAs (miRNAs), small noncoding RNAs that regulate gene expression, downregulate cardiac NFKBIA and activates NF-κB contributing to cardiomyocyte injury in CKD-HFpEF. Methods: Unbiased cardiac miRNA-sequencing was performed in normal and CKD-HFpEF pigs (n=4/group, 2 males/2 females). Differentially expressed (fold change ≥2 and false discovery rate (FDR)≤0.05) miRNAs capable of targeting NFKBIA were identified using miRWalk 3.0 and Target Scan 8.0, further validated by qPCR. To study the impact of CKD-HFpEF on cardiac tissue, cardiomyocites (CM) were exposed for 48 hours to plasma from normal and CKD-HFpEF pigs (n=3 each) and cardiac injury (LDH release) evaluated, and selected miRNAs modulated (mimic, antagomiR). Results: All CKD-HFpEF pigs showed a significant reduction in renal hemodynamics and function compared to controls accompannied by left ventricular hypertrophy (LVH), abnormal diastolic relaxation and LV strain, and increased circulating ANP and BNP levels, underscoring successful developing of CKD-HFpEF.Unbiased miRNA-seq identified 402 miRNAs targeting NFKBIA, of which 13 were broadly conserved among vertebrates and only 4 expressed in pig’s cardiac tissue. Among them, only miR-532-3p was upregulated in myocardium of CKD-HFpEF pigs.Expression of miR-532-3p was also higher in CM exposed to CKD-LVDD plasma or miR-532-3p mimic, associated with down-regulation of NFKBIA and LDH release. Treatment with anti-miR-532-3p decreased miR-532-3p, increased NFKBIA expression, and reduced CM injury. Conclusions: These observations support a role of miR-532-3p in cardiac NF-kB activation in CKD-HFpEF. In turn, these proof-of-concept studies may assist to identify novel therapeutic targets and develop new interventions to protect the heart in CKD. NIH HL095638 (ARC), DK129240 (AE) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.