Proximal tubular MBD2 promotes autophagy to drive the progression of AKI caused by vancomycin via regulation of miR-597-5p/S1PR1 axis.

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.

Guo Y ，Wu D ，Li X ，Wang J ，Li H ，Li Y ，Luo D ，Yi F ，Zhang D ... -  《-》

MBD2 upregulates miR-301a-5p to induce kidney cell apoptosis during vancomycin-induced AKI.

Wang J ，Li H ，Qiu S ，Dong Z ，Xiang X ，Zhang D ... -  《Cell Death & Disease》

Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC-δ.

Xu X ，Pan J ，Li H ，Li X ，Fang F ，Wu D ，Zhou Y ，Zheng P ，Xiong L ，Zhang D ... -  《-》

MiR-6918-5p prevents renal tubular cell apoptosis by targeting MBD2 in ischemia/reperfusion-induced AKI.

Although previous studies reported that miRNAs are involved in the progression of acute kidney injury (AKI), their exact function and mechanism in ischemic AKI remains largely unknown. This study aims to define the role of miR-6918-5p in ischemia-reperfusion AKI. Materials and methods The renal arteries of C57BL/6J mice were clamped to establish a model of ischemia-reperfusion renal injury. BUMPT cells were added with Antimycin A and calcium ionophore to establish a model of ATP depletion in vitro. Cell apoptosis was detected by CCK8, flow cytometry and western blot, while HE staining and TUNEL staining were used to assess the degree of kidney damage. We suppressed mmu_miR-6918-5p by ischemic injury in vitro and in vivo. We found that ischemia-reperfusion (I/R)-induced renal tubular cell apoptosis and the expression of cleaved caspase3 were enhanced by the inhibitor of mmu_miR-6918-5p; this effect was attenuated by an mmu_miR-6918-5p mimic. Mechanistically, mmu_miR-6918-5p binds to the 3' UTR region of MBD2 and represses its expression. The mmu_miR-6918-5p mimic alleviated the ischemic AKI by targeting MBD2. Conversely, the inhibitor of mmu_miR-6918-5p enhanced the ischemic AKI; this was diminished by MBD2-KO. Mmu_miR-6918-5p protected against the development of ischemic AKI by targeting MBD2.

Pan J ，Zhang G ，Hu Y ，Jiang H ，Tang X ，Zhang D ... -  《-》

p53 activates miR-192-5p to mediate vancomycin induced AKI.

Chen J ，Wang J ，Li H ，Wang S ，Xiang X ，Zhang D ... -  《Scientific Reports》