Systems biology approach uncovers candidates for kidney-heart interorgan crosstalk after myocardial infarction

Myocardial infarction (MI) and subsequent heart failure are frequently accompanied by chronic kidney disease, further impairing outcomes and complicating treatment. To better understand heart-kidney crosstalk, we used RNA sequencing data to infer interorgan signalling after experimentally induced MI in mice, focusing on secreted biomolecules and interorgan cross talk that may drive cardiorenal syndrome (CRS). To assess acute and chronic effects, we examined kidneys at 5d and 28d post-MI, evaluating changes in renal gene expression and fibrosis. During the acute phase 5d post-MI, several genes inferred to target kidney receptors were highly upregulated in the cardiac infarct zone, with Postn and Spp1 being the most probable ligands. However, only minor changes in gene expression were detected in the kidney 5d post-MI. At 28d post-MI, renal fibrosis and the number of differentially expressed genes (DEGs) in the kidney increased. Gene ontology enrichment suggested metabolic adaptions as part of a long-term response. Based on upregulated DEGs in kidney 28d post-MI, we suggest two kidney-to-heart interactions: Slitrk6-Ptprs and Gdf15-Tgfbr2. In vitro, GDF-15 treatment of human cardiac fibroblasts induced pro-fibrotic gene expression, mirroring in vivo changes in the heart. Our data suggest that MI in mice elicits minimal acute response in kidney but triggers chronic transcriptional and pro-fibrotic changes in kidney, potentially driven by altered renal metabolism. The inference of interorgan signalling molecules such as GDF-15 points towards candidate mediators of CRS and provides a basis for future mechanistic and clinical studies.