Integrated metabolomic and proteomic analysis reveals mechanistic links between uremia and cardiac remodeling in uremic cardiomyopathy

Abstract Rationale: Chronic kidney disease (CKD) is associated with cardiac alterations including left ventricular hypertrophy, perivascular fibrosis and diastolic and systolic dysfunction typically known as uremic cardiomyopathy (UCM). While the failing heart is characterized by profound metabolic changes, the specific pathomechanism in the uremic heart remains unclear. Metabolomic and proteomic analysis could be a promising approach to gain deeper understanding of UCM. Objective We, therefore, aimed to characterize the metabolic and proteomic signatures of UCM and identify potential biomarkers. Methods A total of 630 metabolites and 4100 proteins were analyzed by mass spectrometry in myocardium and plasma of C57BL/6J mice with acute kidney injury (AKI). AKI was induced by repeated intravenous injection of Shiga toxin 2 (Stx2) until experimental endpoint on day 7. Stx2 binds to globotriaosylceramide (Gb3) on renal endothelial cells, leading to the development of hemolytic-uremic syndrome (HUS) with AKI and uremia without any known primary toxic effects on cardiomyocytes. Results Metabolomic and proteomic analyses indicated enhanced oxidative metabolism, reflected by upregulation of proteins related to β-oxidation, oxidative phosphorylation and additional mitochondrial metabolism, including HIBADH, HADHA, OXSM, and ATP5j, with concordant alterations in metabolic groups such as triacylglycerides, acylcarnitines, and hexoses. Pathway enrichment analysis further indicated activation of mitochondrial fission (e.g., FIS1 and MTFR1L) together with a pro-hypertrophic remodeling pattern involving increased expression of MYH6 and laminins, as well as accumulation of membrane lipid classes including glycosylceramides and sphingomyelins. Uremic toxins, including 1-methylhistidine (1-Met-His), indoxyl sulfate (IS), and trimethylamine N-oxide (TMAO), were significantly increased in both plasma and myocardium. Conclusion The metabolic and proteomic changes in uremic myocardium provide novel mechanistic links of the pathogenesis in UCM. Due to the significant accumulation in both plasma and myocardium, we discuss 1-Met-His, IS and TMAO as potential biomarkers for UCM associated with inflammation and fibrosis. Our study is the first to show cardiac accumulation of uremic toxins in UCM with potential therapeutic implications.