Heart-to-kidney signal by extracellular vesicles promotes kidney injury in cardiorenal syndrome.

Abstract

Aims: Cardiorenal syndrome type-1 (CRS1), defined as acute kidney injury occurring in the setting of acute cardiac illness, is associated with substantial morbidity and mortality. Our objective was to determine whether extracellular vesicles (EVs) derived from the injured heart localize to the kidneys and contribute to renal injury in CRS1, and to elucidate mechanisms by which cardiac-derived EVs mediate kidney damage.

Methods and results: Using cardiomyocyte-specific EV reporter mice, we characterized the release of cardiac-derived EVs and their biodistribution to the kidneys. Acute myocardial infarction increased circulating levels of these EVs and enhanced their uptake by proximal tubular epithelial cells. To directly assess their impact on the kidney, EVs derived from cardiomyocytes cultured under normoxic (N-EV) or hypoxic (H-EV) conditions were injected into the renal arteries of wild-type mice. H-EV, but not N-EV, induced proximal tubular epithelial cell injury and worsening of kidney function. To identify EV biomarkers, we performed proteomic profiling of cargo from N-EV and H-EV, and validated the muscle-specific protein TRIM72 as a biomarker of EVs originating from injured cardiomyocytes. In a porcine CRS1 model, plasma levels of TRIM72 positive-EVs were increased, and we demonstrate their delivery to the kidney. Similarly, in CRS1 patients, higher plasma levels of TRIM72-positive EVs correlated with the development of acute kidney injury. Mechanistically, uptake of H-EVs by proximal tubular epithelial cells induced transcription of lipogenic genes and caused lipid accumulation, whereas lipogenesis blockade protected these cells from H-EV-induced injury. We subsequently found that reduced expression of the transcription factor FOXO3 drove H-EV-induced transcriptomic reprogramming. H-EV cargo was enriched with specific Foxo3-targeting miRNAs, whose delivery promoted proximal tubular epithelial cell cytotoxicity, oxidative stress, and suppressed FOXO3 levels.

Conclusions: Overall, this work demonstrates that a Foxo3-targeting miRNA heart-to-kidney signal mediated by injured cardiac-derived EVs contributes to kidney injury in CRS1.