Adipose c-Jun NH2-terminal kinase promotes angiotensin II-induced and deoxycorticosterone acetate salt-induced hypertension and vascular dysfunction by inhibition of adiponectin production and activation of SGK1 in mice.

Abstract

Adipose c-Jun NH2-terminal kinase 1/2 (JNK1/2) is a central mediator involved in the development of obesity and its complications. However, the roles of adipose JNK1/2 in hypertension remain elusive. Here we explored the role of adipose JNK1/2 in hypertension. The roles of adipose JNK1/2 in hypertension were investigated by evaluating the impact of adipose JNK1/2 inactivation in both angiotensin II (Ang II)-induced and deoxycorticosterone acetate (DOCA) salt-induced hypertensive mice. Specific inactivation of JNK1/2 in adipocytes significantly alleviates Ang II-induced and DOCA salt-induced hypertension and target organ damage in mice. Interestingly, such beneficial effects are also observed in hypertensive mice after oral administration of JNK1/2 inhibitor SP600125. Mechanistically, adipose JNK1/2 acts on adipocytes to reduce the production of adiponectin (APN), then leads to promote serum and glucocorticoid-regulated kinase 1 (SGK1) phosphorylation and increases epithelial Na + channel α-subunit (ENaCα) expression in both renal cells and adipocytes, respectively, finally exacerbates Na + retention. In addition, chronic treatment of recombinant mouse APN significantly augments the beneficial effects of adipose JNK1/2 inactivation in DOCA salt-induced hypertension. By contrast, the blood pressure-lowering effects of adipose JNK1/2 inactivation are abrogated by adenovirus-mediated SGK1 overexpression in Ang II -treated adipose JNK1/2 inactivation mice. Adipose JNK1/2 promotes hypertension and targets organ impairment via fine-tuning the multiorgan crosstalk among adipose tissue, kidney, and blood vessels.