Abstract 4148020: Circulating Extracellular Vesicles-Mediated Cardiotoxicity: A Novel Mechanism Exacerbating Heart Failure in Chronic Kidney Disease

Background: More than 50% of deaths in advanced chronic kidney disease (CKD) are attributed to cardiovascular disease (CVD). The degree of heart failure (HF) correlates with severity of CKD. Clinical observations suggest that kidney-derived factors contribute to the development of HF in CKD, independent of the known co-morbidities such as hypertension and hyperglycemia. However, to date, no kidney-specific risk factor that triggers early damage to the heart has been identified, primarily due to a paucity of studies in patients with reno-cardiac disease. Here, we investigate the role of circulating extracellular vesicles (EVs) from CKD patients in pathological communication from the kidney to the heart, causing cardiotoxicity, impair cardiac function and leading to HF. Methods and Results: We isolated the plasma EVs from patients with CKD (hCKD-EVs) and healthy control (hCtr-EVs) and assayed for their cardiotoxicity both in vitro (human AC16 and rat primary cardiomyocytes (CMs) in culture) and in vivo (intramyocardial injection to Nod-Scid mice). hCKD-EVs significantly induced apoptosis in cultured CMs and in injected mice hearts and impaired the contractility of CMs, compared with hCtr-EVs. We also established an adenine-induced CKD mouse model that developed HF with reduced cardiac function. In line with hCKD-plasma EVs, kidney-derived EVs from CKD mice (mCKD-kidney EVs) induced cardiotoxicity both in vitro and in vivo. Moreover, decreasing the circulating EVs in CKD mice using an inhibitor of EV-biogenesis, GW4869, significantly improved the cardiac function in CKD mice. Small RNA sequencing and qPCR analysis revealed several highly expressed miRNAs in both human and mouse CKD-EVs, which are associated with CM apoptosis. MiRNA mimics treated to AC16 CMs induced their apoptosis, confirming the cardiotoxic function of miRNAs. To demonstrate the renal origin of these CKD-EV-miRNAs, we quantified the levels of corresponding endogenous primary miRNAs. We detected that several CKD-EV-miRNAs are originating from the kidney tissues and specific kidney cells, such as PTCs and podocytes in CKD mice. Conclusion: Our studies establish that both human and mouse CKD EVs are cardiotoxic and impair cardiac function. CKD-EVs carry pro-apoptotic miRNAs and are key contributors to humoral cardiotoxicity in CKD patients. Thus, they have the potential to serve as biomarkers for early diagnosis of and novel therapeutics for chronic reno-cardiac disease.