Abstract
BackgroundN6-Methyladenosine (m6A) modification has been implicated in many bioprocesses. However, its functions in diabetic nephropathy (DN) have not been determined. Here, we investigated the role of METTL14, a key component of the m6A methyltransferase complex, in DN.MethodsThe expression of METTL14 was detected in DN patients and human renal glomerular endothelial cells (HRGECs). In vitro and in vivo experiments were performed to explore the functions of METTL14 on high glocse-induced HRGECs and renal injury of DN mice. We also investigated whether METTL14 works by regulating α-klotho expression through m6A modification.ResultsMETTL14 were highly expressed in kidneys of DN patients and high glocse-induced HRGECs both at the mRNA and protein level. Overexpression of METTL14 increased ROS, TNF-α and IL-6 levels and apoptosis in HRGECs. Conversely, METTL14 silence decreased the levels of ROS, TNF-α and IL-6 and cell apoptosis. We confirmed that METTL14 down-regulated α-klotho expression in an m6A-dependent manner. In addition, we also found that METTL14 aggravated renal injury and inflammation of db/db mice, which could partially rescued by α-klotho.ConclusionOur data revealed that METTL14 plays a vital role in high glucose-induced glomerular endothelial cells and diabetic nephropathy through m6A modification of α-klotho.
Highlights
N6-Methyladenosine (m6A) modification has been implicated in many bioprocesses
We investigated the functions of METTL14 on glomerular endothelial cell injury in vitro and diabetic nephropathy in vivo, and explored whether METTL14 works through mediating m6A modification of α-klotho
METTL14 was highly expressed in diabetic nephropathy (DN) patients and high glucose‐induced human renal glomerular endothelial cells (HRGECs) As shown in Fig. 1, METTL14 was significantly increased in kidney tissues of DN patients both at the mRNA and protein level (Fig. 1A–C)
Summary
N6-Methyladenosine (m6A) modification has been implicated in many bioprocesses. We investigated the role of METTL14, a key component of the m6A methyltransferase complex, in DN. Diabetic nephropathy (DN) is the most common microvascular complication in diabetes and a chronic progressive kidney disease which causes the end-stage renal disease (Vasanth Rao et al 2019). The occurrence and development of DN may be caused by an interaction between inflammation, metabolism, and hemodynamics, which leads to increased glomerular injury and molecular modifications under hyperglycemia conditions (Warren et al 2019; Rayego-Mateos et al 2020). M6A is mediated by a methyltransferase complex, which contained the methyltransferase-like enzymes METTL3 and METTL14 (Liu et al 2020, 2014). The m6A modification regulates the splicing, transport, stability and translation efficiency of RNA, and further participates in the biological
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