BACKGROUND: Cardiovascular disease (CVD) causes more than 50% of deaths in patients with advanced chronic kidney disease (CKD). Clinical studies suggest that kidney-derived factors contribute to CVD development in CKD, independently of co-morbidities. However, to date, no kidney-specific humoral risk factor that triggers direct cardiotoxicity has been identified. In this cross-sectional study, we investigate how, in CKD patients, circulating extracellular vesicles (EVs) facilitate pathological kidney-heart communication, thereby causing cardiotoxicity, impairing cardiac function, and contributing to heart failure (HF) progression.
METHODS: We investigated the function of EVs from CKD patients and adenine diet-induced CKD mice on cardiomyocyte and cardiac contractility. MiRNA cargo of EVs was identified by small RNA sequencing and qRT-PCR, and their cardiotoxicity was tested by using miRNA-mimics. Tissue and cellular origin of CKD-EV-miRNAs were determined from their corresponding primary miRNA expressions in mice.
RESULTS: EVs from plasma of CKD patients, but not from healthy controls, were cardiotoxic; they significantly induced apoptosis both in vitro and in vivo and impaired contractility of adult rat primary cardiomyocytes in vitro. Likewise, EVs from both plasma and kidneys of CKD mice were cardiotoxic. Pharmacologically depleting circulating EVs in CKD mice significantly recovered cardiac function and ameliorated HF, improvements that suggest CKD-EVs play a causal role in HF pathogenesis. Both human and mouse CKD-EVs were enriched in distinct miRNAs, compared to control-EVs. CKD-EV-miRNA mimics were cardiotoxic, impairing contractility and downregulating contractile gene expression in human-iPSC-derived cardiomyocytes. Interestingly, levels of endogenous primary miRNAs corresponding to circulating CKD-EV-miRNAs were significantly higher in CKD-kidney tissues, specifically in CD45CD31renal cells, but not in CKD-hearts, CKD-livers or CKD-PBMCs from peripheral blood, a result that indicates that CKD-EV-miRNAs originate renally. Remarkably, CKD-EV-miRNA levels correlated with established markers of cardiac injury, thus uncovering the presence of sub-clinical heart disease and demonstrating heterogeneity in reno-cardiac disease. -ve -ve
CONCLUSIONS: Collectively, our human subject and mouse studies show that circulating CKD-EVs, carrying distinct renal-derived miRNAs, mediate the molecular crosstalk that contributes to the pathogenesis of HF in CKD. Consequently, CKD-EVs hold promise as diagnostic and prognostic biomarkers for early disease detection and as targets for novel therapeutic interventions in chronic reno-cardiac disease.
