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Cardiac micro-RNA and transcriptomic profile of a novel swine model of chronic kidney disease and left ventricular
Alejandro R Chade1,2,3, Alfonso Eirin4
1Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi.
Insights
Chronic kidney disease (CKD) causes heart failure by altering cardiac gene expression. This study reveals specific microRNA and mRNA changes linked to cardiac remodeling and metabolic dysfunction in a swine model, offering new therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Nephrology
- Molecular Biology
Background:
- Chronic kidney disease (CKD) is a significant independent risk factor for heart failure development.
- The precise molecular mechanisms linking CKD to cardiac dysfunction, particularly left ventricular diastolic dysfunction (LVDD), remain largely unknown.
- Cardiovascular disease accounts for over 50% of deaths in patients with progressive CKD.
Purpose of the Study:
- To investigate the hypothesis that CKD alters cardiac microRNA (miRNA) and transcriptomic profiles.
- To identify molecular pathways associated with cardiac remodeling and metabolic processes in CKD-induced LVDD.
- To characterize these changes in a novel translational swine model of CKD and cardiac dysfunction.
Main Methods:
- Utilized a translational swine model with induced CKD and subsequent cardiac dysfunction (CKD-LVDD) over 14 weeks.
- Quantified renal and cardiac hemodynamics using multidetector CT and echocardiography.
- Performed cardiac miRNA and mRNA sequencing (seq) in a subset of pigs, validated by qPCR, and conducted confirmatory ex vivo studies.
Main Results:
- Identified significant differential expression of miRNAs and mRNAs in CKD-LVDD pigs compared to controls (e.g., 9 miRNAs upregulated, 172 downregulated).
- Integrated miRNA/mRNA analysis revealed dysregulated gene targets involved in cardiac remodeling, ubiquitination, ATP/fatty acid synthesis, and extracellular matrix remodeling.
- Observed abnormal diastolic relaxation, mitochondrial injury, LV fibrosis, and myocardial lipid accumulation in CKD-LVDD pig hearts.
Conclusions:
- Comprehensively characterized the cardiac miRNA and transcriptomic profile in a translational model of CKD-LVDD.
- Identified dysregulated genes associated with cardiac remodeling and fatty acid metabolism, potentially regulated post-transcriptionally early in CKD.
- These findings provide a foundation for targeted research into LVDD pathophysiology and the development of novel therapeutic interventions to reduce cardiovascular morbidity in CKD.
Abstract:
Chronic kidney disease (CKD) is an independent risk factor for the development of heart failure, but the underlying mechanisms remain unknown. Using a novel translational swine model of CKD and cardiac dysfunction, we hypothesize that CKD alters the cardiac miRNA and transcriptomic profile that associate with cardiac remodeling and metabolic processes implicated in the development of left ventricular diastolic dysfunction (CKD-LVDD). CKD-LVDD and normal control pigs (n = 6 each) were studied for 14 wk. Renal and cardiac hemodynamics were quantified by multidetector CT and echocardiography. In randomly selected pigs (n = 3/group), cardiac miRNA- and mRNA-sequencing (seq) was performed, validated (qPCR), and followed by confirmatory ex vivo studies. Differential expression analysis identified nine miRNAs and 125 mRNAs upregulated and 17 miRNAs and 172 mRNAs downregulated [fold-change ≥ 2, and false discovery rate (FDR) ≤ 0.05] in CKD-LVDD versus normal controls. Integrated miRNA-/mRNA-seq analysis identified 71 overlappings downregulated mRNA targets of miRNAs upregulated, and 39 overlappings upregulated mRNA targets of miRNAs downregulated in CKD-LVDD versus controls. Functional analysis showed that these genes were primarily implicated in processes associated with cardiac remodeling, including ubiquitination, ATP and fatty acid synthesis, and extracellular matrix remodeling. In agreement, hearts of CKD-LVDD pigs exhibited abnormal diastolic relaxation, mitochondrial injury, moderate LV fibrosis, and myocardial lipid accumulation. Our work comprehensively characterizes the cardiac micro-RNA and transcriptomic profile of a translational model of CKD-LVDD. Our data may set the foundation for new targeted studies to further elucidate LVDD pathophysiology and assist to develop therapeutic interventions.NEW & NOTEWORTHY Chronic kidney disease (CKD) is a progressive disorder in which more than 50% of deaths are attributed to cardiovascular disease. Using a swine model of CKD that develops left ventricular dysfunction (CKD-LVDD), we characterize the cardiac micro-RNA and transcriptomic profile, identifying dysregulated genes associated with cardiac remodeling and fatty acid metabolism that might be post-transcriptionally regulated early in the disease. These findings pinpointed pathological pathways that may open new avenues toward therapeutic research to reduce cardiovascular morbidity in CKD.
