RESUMO

The influence of a single gene on the pathogenesis of essential hypertension may be difficult to ascertain, unless the gene interacts with other genes that are germane to blood pressure regulation. G-protein-coupled receptor kinase type 4 (GRK4) is one such gene. We have reported that the expression of its variant hGRK4γ(142V) in mice results in hypertension because of impaired dopamine D1 receptor. Signaling through dopamine D1 receptor and angiotensin II type I receptor (AT1R) reciprocally modulates renal sodium excretion and blood pressure. Here, we demonstrate the ability of the hGRK4γ(142V) to increase the expression and activity of the AT1R. We show that hGRK4γ(142V) phosphorylates histone deacetylase type 1 and promotes its nuclear export to the cytoplasm, resulting in increased AT1R expression and greater pressor response to angiotensin II. AT1R blockade and the deletion of the Agtr1a gene normalize the hypertension in hGRK4γ(142V) mice. These findings illustrate the unique role of GRK4 by targeting receptors with opposite physiological activity for the same goal of maintaining blood pressure homeostasis, and thus making the GRK4 a relevant therapeutic target to control blood pressure.

Assuntos

Benzimidazóis/farmacologia , Pressão Sanguínea/fisiologia , Quinase 4 de Receptor Acoplado a Proteína G/genética , Regulação da Expressão Gênica , Histona Desacetilase 1/antagonistas & inibidores , Hipertensão/genética , Receptor Tipo 1 de Angiotensina/genética , Tetrazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Compostos de Bifenilo , Modelos Animais de Doenças , Hipertensão Essencial , Feminino , Quinase 4 de Receptor Acoplado a Proteína G/biossíntese , Células HEK293 , Histona Desacetilase 1/metabolismo , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Immunoblotting , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 1 de Angiotensina/biossíntese , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa