GRK4 causes renal mitochondrial dysfunction and hypertension by accelerating COX6B1 mRNA attenuation via Lamin A/C phosphorylation and METTL14 upregulation

ABSTRACT: Background: G-protein-coupled receptor kinase 4 (GRK4) and mitochondria are involved in the pathogenesis of hypertension. However, whether renal GRK4 regulates mitochondrial function in hypertension is unknown. Methods: Blood pressure and renal tubular mitochondrial ultrastructure and function were investigated in GRK4 142V transgenic mice and mice with renal tubule-specific overexpression of cytochrome c oxidase subunit 6B1 (COX6B1). The total N6-methyladenosine (m6A) abundance was determined by dot blot assay. Results: GRK4 142V mice had renal mitochondrial structural abnormalities and dysfunction and hypertension. Proteomics showed that reduced COX6B1, a mitochondrial associated protein, ranked first among altered candidates. AAV9-mediated renal tubule Cox6b1 rescue normalized the blood pressure and renal mitochondrial abnormalities in GRK4 142V mice. Liquid chromatography-tandem mass spectrometry and phospho-proteomic analysis identified nuclear envelope proteins Lamin A/C, encoded by LMNA, as a putative protein that bind to GRK4. The interaction of GRK4 and Lamin A/C, and levels of phosphorylated Lamin A/C were increased in GRK4 142V-transduced renal tubule cells. Moreover, GRK4 142V cells had increased RNA m6A methylation and METTL14 expression, which are downstream of Lamin A/C. Phospho-proteomics revealed that GRK4 phosphorylated Lamin A/C at threonine 394 (T394), whose non-phosphorylatable mutation (T394A) effectively prevented the reduction of COX6B1 expression and abolished the elevated of METTL14 expression in GRK4 142V cells. METTL14 silencing rescued the GRK4 142V-mediated reduction of COX6B1 expression and mRNA attenuation. Conclusions: GRK4-mediated Lamin A/C phosphorylation increased METTL14 expression and RNA m⁶A methylation, which accelerated COX6B1 mRNA attenuation, thereby causing mitochondrial dysfunction and subsequently hypertension.

ORGANISM(S): Rattus Norvegicus

SUBMITTER: Jian Yang  

PROVIDER: PXD084134 | iProX | Sun Sep 13 00:00:00 GMT+01:00 2026

REPOSITORIES: iProX