Abstract
Our recent investigation has indicated that the global deletion of MBD2 can mitigate the progression of AKI induced by VAN. Nevertheless, the role and regulatory mechanisms of proximal tubular MBD2 in this pathophysiological process have yet to be elucidated. Our preceding investigation revealed that autophagy played a crucial role in advancing AKI induced by VAN. Consequently, we postulated that MBD2 present in the proximal tubule could upregulate the autophagic process to expedite the onset of AKI. In the present study, we found for the first time that MBD2 mediated the autophagy production induced by VAN. Through the utilization of miRNA chip analysis, we have mechanistically demonstrated that MBD2 initiates the activation of miR-597-5p through promoter demethylation. This process leads to the suppression of S1PR1, which results in the induction of autophagy and apoptosis in renal tubular cells. Besides, PT-MBD2-KO reduced autophagy to attenuate VAN-induced AKI via regulation of the miR-597-5p/S1PR1 axis, which was reversed by rapamycin. Finally, the overexpression of MBD2 aggravated the diminished VAN-induced AKI in autophagy-deficient mice (PT-Atg7-KO). These data demonstrate that proximal tubular MBD2 facilitated the process of autophagy via the miR-597-5p/S1PR1 axis and subsequently instigated VAN-induced AKI through the induction of apoptosis. The potentiality of MBD2 being a target for AKI was established.