Circulating Extracellular Vesicles in Human Cardiorenal Syndrome Promote Renal Injury

BackgroundCardiorenal syndrome (CRS)--renal injury during heart failure (HF)--is linked to higher morbidity. Whether circulating extracellular vesicles (EVs) and their RNA cargo directly impact its pathogenesis remains unclear. MethodsUsing a microfluidic kidney chip model (KC), we investigated transcriptional effects of circulating EVs from patients with CRS on renal epithelial/endothelial cells. We used small RNA-seq on circulating EVs and regression to prioritize subsets of EV miRNAs associated with serum creatinine, a biomarker of renal function. In silico pathway analysis, human genetics, and interrogation of expression of miRNA target genes in the KC model and in a separate cohort of individuals post-renal transplant with microarray-based gene expression was performed for validation. ResultsRenal epithelial and endothelial cells in the KC model exhibited uptake of EVs. EVs from patients with CRS led to higher expression of renal injury markers (IL18, NGAL, KIM1) a greater cystatin C secretion relative to non-CRS EVs. Small RNA-seq and regression identified 15 miRNAs related to creatinine, targeting 1143 gene targets specifying pathways relevant to renal injury, including TGF-b and AMPK signaling. We observed directionally consistent changes in expression of TGF-b pathway members (BMP6, FST, TIMP3) in KC model exposed to CRS EVs, as well as in renal tissue after transplant rejection. Mendelian randomization suggested a role for FST in renal function. ConclusionEVs from patients with CRS directly elicit adverse transcriptional and phenotypic responses in a KC model by regulating biologically relevant pathways, suggesting a novel role for EVs in CRS. Trial RegistrationClinicalTrials.gov NCT 03345446. FundingAHA (SFRN16SFRN31280008), NHLBI (1R35HL150807-01) and NCATS (UH3 TR002878).