Inhibition of MiR-106b-5p mediated by exosomes mitigates acute kidney injury by modulating transmissible endoplasmic reticulum stress and M1 macrophage polarization.

Acute kidney injury (AKI), mainly caused by Ischemia/reperfusion injury (IRI), is a common and severe life-threatening disease with high mortality. Accumulating evidence suggested a direct relationship between endoplasmic reticulum (ER) stress response and AKI progression. However, the role of the transmissible ER stress response, a new modulator of cell-to-cell communication, in influencing intercellular communication between renal tubular epithelial cells (TECs) and macrophages in the AKI microenvironment remains to be determined. To address this issue, we first demonstrate that TECs undergoing ER stress are able to transmit ER stress to macrophages via exosomes, promoting macrophage polarization towards the pro-inflammatory M1 phenotype in vitro and in vivo. Besides, the miR-106b-5p/ATL3 signalling axis plays a pivotal role in the transmission of ER stress in the intercellular crosstalk between TECs and macrophages. We observed an apparent increase in the expression of miR-106b-5p in ER-stressed TECs. Furthermore, we confirmed that ALT3 is a potential target protein of miR-106b-5p. Notably, the inhibition of miR-106b-5p expression in macrophages not only restores ATL3 protein level but also decreases transmissible ER stress and hinders M1 polarization, thus alleviating AKI progression. Additionally, our results suggest that the level of exosomal miR-106b-5p in urine is closely correlated with the severity of AKI patients. Taken together, our study sheds new light on the crucial role of transmissible ER stress in the treatment of AKI through the regulation of the miR-106b-5p/ATL3 axis, offering new ideas for treating AKI.