Macrophage-derived exosomal miR-195a-5p impairs tubular epithelial cells mitochondria in acute kidney injury mice

Macrophages (M phi) infiltration is a common characteristic of acute kidney injury (AKI). Exosomes-mediated cell communication between tubular epithelial cells (TECs) and M phi has been suggested to be involved in AKI. Exosomes-derived from injured TECs could regulate M phi polarization during AKI. However, little is known regarding how activated M phi regulates kidney injury. To explore the role of activated M phi in the AKI process, we revealed that M phi-derived exosomes from AKI mice (Exos(AKI)) caused mitochondria damage and induced TECs injury. Then, we detected the global miRNA expression profiles of M phi(NC) and M phi(AKI) and found that among the upregulated miRNAs, miR-195a-5p, which regulates mitochondria metabolism in cancer, was significantly increased in M phi(AKI). Due to the enrichment of miR-195a-5p in Exos(AKI), the miR-195a-5p level in the kidney was elevated in AKI mice. More interestingly, based on the high expression of pri-miR-195a-5p in kidney-infiltrated M phi, and the reduction of miR-195a-5p in kidney after depletion of M phi in AKI mice, we confirmed that miR-195a-5p may be produced in infiltrated M phi, and shuttled into TECs via Exos(M phi). Furthermore, in vitro inhibition of miR-195a-5p alleviated the effect of Exos(AKI) induced mitochondrial dysfunction and cell injury. Consistently, antagonizing miR-195a-5p with a miR-195a-5p antagomir attenuated cisplatin-induced kidney injury and mitochondrial dysfunction in mice. These findings revealed that the M phi exosomal miR-195a-5p derived from AKI mice played a critical pathologic role in AKI progression, representing a new therapeutic target for AKI.