METTL3-mediated m6A modification of TIMP2 mRNA promotes podocyte injury in diabetic nephropathy

Epigenetic changes are present in many physiological and pathological processes. The N-6-methyladenosine (m6A) modification is the most common modification in eukaryotic mRNA. However, the role of m6A modification in diabetic nephropathy (DN) remains elusive. Here, we found that m6A modification was significantly upregulated in the kidney of type 1 and type 2 diabetic mice, which was caused by elevated levels of METTL3. Moreover, METTL3 is increased in podocyte of renal biopsy from patients with DN, which is related to renal damage. METTL3 knockout significantly reduced the inflammation and apoptosis in high glucose (HG)-stimulated podocytes, while its overexpression significantly aggravated these responses in vitro. Podocyte-conditional knockout METTL3 significantly alleviated podocyte injury and albuminuria in streptozotocin (STZ)-induced diabetic mice. Therapeutically, silencing METTL3 with adeno-associated virus serotype-9 (AAV9)-shMETTL3 in vivo mitigated albuminuria and histopathological injury in STZ-induced diabetic mice and db/db mice. Mechanistically, METTL3 modulated Notch signaling via the m6A modification of TIMP2 in an insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2)-dependent manner and exerted pro-inflammatory and pro-apoptotic effects. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of podocyte injury in DN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of DN.

Automated summary

Epigenetic changes, specifically the N-6-methyladenosine (m6A) modification, play a crucial role in diabetic nephropathy (DN). This study demonstrates that METTL3-mediated m6A modification is an important mechanism in podocyte injury in DN. Elevated METTL3 levels lead to increased inflammation and apoptosis, while METTL3 knockout alleviates these responses. Silencing METTL3 shows therapeutic potential in mitigating kidney injury and albuminuria in diabetic mice. METTL3 modulates Notch signaling through m6A modification of TIMP2, exerting pro-inflammatory and pro-apoptotic effects.