https://doi.org/10.1007/s00392-025-02625-4
1Universitäts-Herzzentrum Freiburg - Bad Krozingen Klinik für Kardiologie und Angiologie Freiburg im Breisgau, Deutschland
Background:
Myocardial infarction (MI) often leads to heart failure, which is frequently accompanied by chronic kidney disease (CKD), a condition that worsens patient prognosis and complicates treatment. The interplay between heart and kidney following MI could reveal pathways that affect both cardiac repair and renal response, presenting new opportunities for therapeutic intervention.
Objectives:
This study aims to analyse inter-organ crosstalk in a murine model of left anterior descending (LAD) artery ligation, focusing on how the secretome from the infarcted heart or diseased kidney might influence the other organs function and pathology. By examining transcriptional changes and predicting ligand-receptor interactions, we want to clarify how signals from an infarcted heart could impact kidney health and, conversely, how kidney responses may affect cardiac post-MI remodelling.
Experimental design and Methods:
We performed RNA sequencing on murine hearts 5 days post LAD-ligation, analysing tissue from the infarct zone, remote zone, and sham controls. Additionally, RNA sequencing of kidneys was conducted at 5 and 28 days post-MI to capture temporal changes.
Results:
In the kidney, only 18 genes were significantly regulated at 5 days post-MI compared to sham, while 86 genes showed differential expression at 28 days. In contrast, the infarct zone of the heart exhibited substantial transcriptional changes, with 11,120 genes differentially regulated 5 days post-MI, and 1,913 genes significantly altered in the remote zone. To reveal possible interactions between heart and kidney, we focused on genes encoding secreted proteins. In the infarct zone, 624 differentially expressed genes (DEGs) coding for secreted proteins were identified. A gene ontology (GO) enrichment analysis revealed that most of the enriched GO terms were linked to extracellular matrix remodelling or inflammation.
Using the CellChat R package, we mapped potential ligand-receptor interactions between heart and kidney. We identified 23 ligands significantly upregulated in the infarcted heart, with corresponding highly-expressed receptors in kidney, emphasizing potential pathways for heart-kidney signalling post-MI. Notably, three DEGs in the kidney at 28 days were also predicted to target receptors in the heart.
Summary:
Our findings suggest a dynamic, time-dependent interaction between the heart and kidney following MI, with specific ligand-receptor pairs mediating cross-organ communication. These pathways could play a role in both cardiac and renal remodelling, providing insights into therapeutic strategies for improving outcomes post-MI.
Outlook:
To further understand the biological impact of our predicted target proteins, we plan to validate their effects on different cardiac and renal cell types in cell culture. Additionally, we plan to test the presence of these proteins in serum of patients with heart failure or acute MI, with and without kidney disease, to assess their potential relevance in human pathology.