Abstract
Nephrotoxicity of colistin is the major factor limiting its clinical application. However, the exact mechanism of colistin-induced nephrotoxicity is still elusive. N6-Methyladenosine (m6A) modification has been implicated in many biological processes, however, its role in colistin-induced nephrotoxicity needs to be elucidated. Mouse renal tubular epithelial cells (mRTECs) were treated with 200 μM colistin with or without METTL3 overexpression. Cells injury, m6A assay, oxidative stress and apoptosis were examined. Levels of m6A are decreased after colistin treatment in mRTECs. METTL3 is the major factor involved in abnormal m6A modification. METTL3 overexpression plays a protective role against colistin-induced oxidative stress and apoptosis. Moreover, METTL3 interacts with the microprocessor protein DGCR8 and positively modulates miR-873-5p mature process in an m6A-dependent manner. Further experiments show that miR-873-5p could regulate Keap1-Nrf2 pathway against colistin-induced oxidative stress and apoptosis. These studies revealed an important role of METTL3/m6A in colistin-induced nephrotoxicity and provide a new insight on m6A modification in drug induced toxicity.
Highlights
Researchers extensively demonstrated the increasing proportion of infections caused by multi-drug resistant and pandrug-resistant gram-negative bacteria and the lack of effective treatment drugs, and colistin has become an important choice for the treatment of such infections (Li et al, 2006; Wadl et al, 2010; Hawkey, 2015; Aliyu et al, 2017; Rodrigo-Troyano and Sibila, 2017)
The results showed that miR-873-5p was regulated by METTL3-mediated m6A modification, which enhanced DGCR8 recognition of pri-miR-873, promoted the generation of mature miR-873-5p, miR-873-5p targeted inhibition of Keap1, and activated the Nrf2/HO-1 pathway
METTL3 was overexpressed in Mouse renal tubular epithelial cells (mRTECs) and the results showed that the decrease of METTL3 expression was the main reason for the decrease of m6A levels caused by colistin (Figure 2C)
Summary
Researchers extensively demonstrated the increasing proportion of infections caused by multi-drug resistant and pandrug-resistant gram-negative bacteria and the lack of effective treatment drugs, and colistin has become an important choice for the treatment of such infections (Li et al, 2006; Wadl et al, 2010; Hawkey, 2015; Aliyu et al, 2017; Rodrigo-Troyano and Sibila, 2017). It has been reported that colistin can cause cough, bronchial contraction and chest distress after inhalation (Dijkmans et al, 2015; Loho and Dharmayanti, 2015). Except nephrotoxicity, the incidence of other adverse reactions of colistin is low and symptoms are mild, which can be recovered after drug withdrawal. Neurotoxicity is one of the main adverse reactions of colistin, but in the past few decades, reports of neurotoxicity caused by this drug are rare (Gupta et al, 2009; Weinstein et al, 2009). Nephrotoxicity is the most common adverse reactions of colistin and it is necessary to clarify the underlying mechanism of colistin-induced renal injury
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