Irisin lowers blood pressure in Zucker diabetic rats by regulating the functions of renal angiotensin II type 1 receptor via the inhibition of the NF-κB signaling pathway

Abstract

Background: Irisin, a novel myokine, has been identified to exert a series of favorable effects on metabolic diseases, including diabetes and obesity. This study aimed to explore the effects of chronic irisin administration on blood pressure and the related underlying mechanisms in Zucker diabetic fatty (ZDF) rats.

Methods and results: Male ZDF rats and Zucker lean (ZL) rats received a continuous subcutaneous infusion of irisin or saline for 4 weeks. Compared with ZL counterparts, ZDF rats reported higher systolic blood pressure (SBP), severer renal inflammation, increased oxidative stress, and impaired natriuresis and diuresis; they also had an elevated AT₁R expression in renal cortex and augmented candesartan-induced natriuresis and diuresis. The irisin administration lowered SBP, improved diuretic and natriuretic effects, and reduced renal inflammation and oxidative stress in ZDF rats, along with decreased renal expression of AT₁R and restored candesartan-mediated natriuresis and diuresis. Further experiments showed that irisin inhibited the translocation of NF-κB from the cytosol to the nucleus and the activation of NF-κB signaling pathway, which may contribute to the reduced AT₁R expression and function.

Conclusions: Irisin administration serves an anti-hypertensive role in ZDF rats by alleviating renal inflammation and oxidative stress, reducing the expression and impact of AT₁R, and restoring natriuresis and diuresis. The underlying mechanism may involve the irisin-induced inhibition of the NF-κB signaling pathway.

Keywords: Angiotensin II type 1 receptor; Hypertension; Irisin; Nuclear factor-kappa B.