METTL3 enhances NSD2 mRNA stability to reduce renal impairment and interstitial fibrosis in mice with diabetic nephropathy

Abstract

Background Nuclear receptor-binding SET domain protein 2 (NSD2) is a histone methyltransferase that has been demonstrated to regulate insulin secretion and glucose concentration. This study focused on the role of NSD2 in the renal impairment during diabetic nephropathy (DN). Methods Serum NSD2 level in patients with DN was examined, and its correlations with the renal impairment-related indicators were examined. A murine model of DN was established, and mouse mesangial cells (SV40-MES-13) were treated with high-glucose (HG) to mimic a DN-like condition in vitro. Overexpression of NSD2 was introduced into mice or cells for in vivo and in vitro studies. The m6A level in HG-treated SV40-MES-13 cells was analyzed. METTL3 expression and its correlation with NSD2 were determined. Results NSD2 was poorly expressed in the serum of patients with DN and was negatively correlated with the levels of fasting blood sugar (FBG), serum creatinine (SCr), serum cystatin C (S-Cys-C), the 24-h urine protein (24-h U-protein) and the urine cystatin C (U-Cys-C). NSD2 overexpression reduced the kidney weight and reduced renal impairment in mice. It also suppressed interstitial fibrosis in mouse kidney tissues and reduced fibrosis-related markers in HG-treated SV40-MES-13 cells. HG treatment reduced the m6A level in the cells. METTL3 promoted m6A modification of NDS2 mRNA and enhanced its stability by YTHDF1. METTL3 overexpression alleviated renal impairment and fibrosis in vivo and in vitro. But the protective role was blocked upon NSD2 silencing. Conclusion This study demonstrates that METTL3 promotes NSD2 mRNA stability by YTHDF1 to alleviate progression of DN.

FTO‐mediated m6A modification of serum amyloid A2 mRNA promotes podocyte injury and inflammation by activating the NF‐κB signaling pathway

“…METTL3 exerts reno-protective effects by upregulating the expression of NSD2 with m6A modification. 28 In the present study, we verified that m6A levels are reduced by m6A spot blotting, whereas the expression of FTO was increased in high glucose-stimulated podocytes. Further, qRT-PCR and Western blot analysis showed that upregulation of FTO was associated with podocyte damage.…”

A bibliometric analysis of RNA methylation in diabetes mellitus and its complications from 2002 to 2022

“…Compared with db/m mice, in the renal tissue of streptozotocin-induced diabetic mice and db/db mice, m 6 A modification levels and METTL3 levels were significantly increased ( 30 ). In high-glucose-treated mouse mesangial cell lines, the m 6 A level was reduced, and the serum level of METTL3 was reduced in patients with DN compared with healthy individuals ( 31 ). In HK2, the decreased mRNA expressions of FTO, METTL3, and METTL14 were reported ( 32 ).…”

“…Another study reported the overexpression of METTL14 reversed highglucose-activated phosphatidylinositol-3-kinase/protein kinase B (P13K/Akt) pathway inactivation in HK2 by enhancing phosphatase and tensin homolog (PTEN), followed by the downregulation of histone deacetylase 5 (HDAC5), thus ameliorating DN manifestations such as fibrosis, inflammation, cell death, and albuminuria (32,49). Overexpression of METTL3 enhanced the stability and expression of nuclear receptor-binding SET domain protein 2 (NSD2) in the high-glucose-induced mouse mesangial cell lines and that NSD2 overexpression attenuated pathological changes in the kidney, including glomerular dilatation, glomerulosclerosis, thylakoid proliferation, and interstitial fibrosis (31). METTL3 was highly expressed in the podocytes of db/db mice and streptozotocin-induced mice compared with db/m mice, and the upregulated expression of METTL3 in podocytes induced by high glucose accounted for the aberrant m 6 A modification.…”

m6A mRNA methylation: Biological features, mechanisms, and therapeutic potentials in type 2 diabetes mellitus

“…In in vivo and in vitro DN models, METTL3 was reported to enhance m 6 A modification of nuclear receptor-binding SET domain protein 2 (NSD2) mRNA and its stability through YTHDF1, thus alleviating high-glucose (HG)-induced renal injury (Figure 5). 137 The mRNA and protein expression levels of METTL14 were highly upregulated in the kidneys of patients with DN and human renal glomerular endothelial cells (HRGECs). Mechanistically, upregulated METTL14 triggers glomerular endothelial cell injury and DN in db/db mice through m 6 A modification of α-klotho (Figure 5).…”