MBD2 mediates renal cell apoptosis via activation of Tox4 during rhabdomyolysis-induced acute kidney injury.

Our study investigated the role of Methyl-CpG-binding domain protein 2 (MBD2) in RM-induced acute kidney injury (AKI) both in vitro and in vivo. MBD2 was induced by myoglobin in BUMPT cells and by glycerol in mice. MBD2 inhibition via MBD2 small interfering RNA and MBD2-knockout (KO) attenuated RM-induced AKI and renal cell apoptosis. The expression of TOX high mobility group box family member 4 (Tox4) induced by myoglobin was markedly reduced in MBD2-KO mice. Chromatin immunoprecipitation analysis indicated that MBD2 directly bound to CpG islands in the Tox4 promoter region, thus preventing promoter methylation. Furthermore, siRNA inhibition of Tox4 attenuated myoglobin-induced apoptosis in BUMPT cells. Finally, MBD2-KO mice exhibited glycerol-induced renal cell apoptosis by inactivation of Tox4. Altogether, our results suggested that MBD2 plays a role in RM-induced AKI via the activation of Tox4 and represents a potential target for treatment of RM-associated AKI.

Sun T ，Liu Q ，Wang Y ，Deng Y ，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》

MBD2 Mediates Septic AKI through Activation of PKCη/p38MAPK and the ERK1/2 Axis.

Our previous study demonstrated that the methyl-CpG-binding domain protein 2 (MBD2) mediates vancomycin (VAN)-induced acute kidney injury (AKI). However, the role and regulation of MBD2 in septic AKI are unknown. Herein, MBD2 was induced by lipopolysaccharide (LPS) in Boston University mouse proximal tubules (BUMPTs) and mice. For both in vitro and in vivo experiments, we showed that inhibition of MBD2 by MBD2 small interfering RNA (siRNA) and MBD2-knockout (KO) substantially improved the survival rate and attenuated both LPS and cecal ligation and puncture (CLP)-induced AKI, renal cell apoptosis, and inflammatory factor production. Global genetic expression analyses and in vitro experiments suggest that the expression of protein kinase C eta (PKCη), caused by LPS, is markedly suppressed in MBD2-KO mice and MBD2 siRNA, respectively. Mechanistically, chromatin immunoprecipitation (ChIP) analysis indicates that MBD2 directly binds to promoter region CpG islands of PKCη via suppression of promoter methylation. Furthermore, PKCη siRNA improves the survival rate and attenuates LPS-induced BUMPT cell apoptosis and inflammatory factor production via inactivation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK)1/2, which were further verified by PKCη siRNA treatment in CLP-induced AKI. Finally, MBD2-KO mice exhibited CLP-induced renal cell apoptosis and inflammatory factor production by inactivation of PKCη/p38MAPK and ERK1/2 signaling. Taken together, the data indicate that MBD2 mediates septic-induced AKI through the activation of PKCη/p38MAPK and the ERK1/2 axis. MBD2 represents a potential target for treatment of septic AKI.

Xie Y ，Liu B ，Pan J ，Liu J ，Li X ，Li H ，Qiu S ，Xiang X ，Zheng P ，Chen J ，Yuan Y ，Dong Z ，Zhang D ... -  《Molecular Therapy-Nucleic Acids》

Rhabdomyolysis-Induced AKI Was Ameliorated in NLRP3 KO Mice via Alleviation of Mitochondrial Lipid Peroxidation in Renal Tubular Cells.

Song SJ ，Kim SM ，Lee SH ，Moon JY ，Hwang HS ，Kim JS ，Park SH ，Jeong KH ，Kim YG ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

EGFR mediated the renal cell apoptosis in rhabdomyolysis-induced model via upregulation of autophagy.

Rhabdomyolysis is a life-threatening condition. One of the most common complications of rhabdomyolysis is acute kidney injury (AKI), and 10 % of all AKI patients present with rhabdomyolysis. EGFR is associated with different types of AKI. However, the function and regulatory mechanism of EGFR in rhabdomyolysis-induced AKI model remain unknown. Here, we performed the experiments to explore the role of EGFR in this model. We used proximal tubule-specific Atg7 knockout mice and Wa-2 mice to establish animal models. Then, the samples were collected for pathology assay and IB detection. In vitro, the BUMPT cells treated with myoglobin were collected for the detection of apoptosis and autophagy. IB detection were processed for the analysis of protein expressions, FCM analysis for the cell apoptosis, GFP-LC3 transfection and immunofluorescent for autophagy. EGFR promotes autophagy to mediate rhabdomyolysis-induced AKI via STAT3/Atg7 axis, and gefitinib is a potential therapeutic option for AKI. Here, we demonstrated that EGFR was activated by myoglobin and glycerol both in vitro and in vivo, respectively. Genetic or pharmacological inhibition of EGFR ameliorated myoglobin and glycerol-induced renal cell apoptosis. Mechanistically, EGFR mediated autophagy induction via STAT3/Atg7 axis, thereby resulting in kidney cell apoptosis. Furthermore, Wa-2 mice or gefitinib treatment prevented the progression of rhabdomyolysis-induced AKI as well as renal cell apoptosis and autophagy via inhibiting STAT3/Atg7 axis. Researchers can use this finding to better study the function and regulatory mechanism of EGFR in RM-induced AKI model. And gefitinib represents a potential target for treatment of AKI.

Sun T ，Wu D ，Deng Y ，Zhang D ... -  《-》