METTL3 mitigates angiotensin II-induced renal hypertensive injury by regulating fatty acid oxidation.

Hypertension is a major contributor to cardiovascular diseases and all-cause mortality worldwide. It can cause damage to multiple target organs, with the kidneys being particularly susceptible. Conditional knockdown of methyltransferase-like 3 (METTL3), an enzyme that mediates N6-methyladenosine modification, has been shown to improve cardiovascular remodeling and reduce blood pressure; however, the underlying mechanisms remain unclear. In this study, we investigated how METTL3 influences hypertension using integrated proteomic and metabolomic analyses. METTL3-knockdown mice were treated with angiotensin II to induce hypertension, followed by proteomic and metabolomic profiling of kidney tissue to identify METTL3-related target proteins and pathways. Hypertension was found to upregulate METTL3 in the kidneys, disrupt fatty acid metabolism, and downregulate proteins involved in mitochondrial energy metabolism. Moreover, conditional knockdown of METTL3 in endothelial cells led to decreased blood pressure in hypertensive mice and a gradual normalization of both fatty acid and energy metabolism. Collectively, these findings suggest that hypertension-induced upregulation of METTL3 contributes to mitochondrial damage and fatty acid metabolism dysregulation. Conditional knockdown of METTL3, in contrast, mitigates mitochondrial injury, restores fatty acid metabolism, and promotes recovery from hypertensive kidney damage, highlighting METTL3 as a potential therapeutic target for hypertension.