Salusin α counteracts salusin β to attenuate artery medial calcification through the inhibition of oxidative stress and extracellular signal-regulated protein kinases signaling pathway in rats with chronic kidney disease.

BACKGROUND: Arterial medial calcification (AMC) is closely associated with morbidity and mortality in people with chronic kidney disease (CKD). Endogenous bioactive peptides, salusin α and salusin β, are alternative splicing products from preprosalusin encoded by the torsion dystonia-related gene. The present study was designed to explore their roles and mechanisms in AMC under CKD condition. CKD rats with AMC were induced by feeding an adenine (0.75%) with high phosphorus (1.5%) diet for 4 weeks. Calcification in A7r5 cells (rat thoracic aorta smooth muscle cells) was induced with calcifying media. The results showed that in rats with CKD and in the calcifying media-treated A7r5 cells, salusin α protein level was reduced, whereas salusin β was elevated in plasma, in aorta and in A7r5 cells, respectively. Calcification, osteogenic transition, oxidative stress, and extracellular signal-regulated protein kinases (ERK) activation were significantly induced, and these changes were effectively reversed by salusin α application, but notably promoted by salusin β administration. More importantly, salusin α or the ERK activation inhibitor U0126 pretreatment in vitro attenuated the promoting effects of salusin β on calcification, osteogenic transition and oxidative stress and ERK activation which also were alleviated by U0126 treatment in vivo. This study indicates that salusin α can attenuate AMC and counteract the promoting effect of salusin β on AMC by inhibiting oxidative stress and the activation of ERK signaling pathway, suggesting that upregulating the expression of salusin α, but downregulating the expression of salusin β in aorta, may be a good strategy for the treatment of vascular calcification under CKD condition.

SIGNIFICANCE STATEMENT: The current study found that bioactive peptides, salusin α and salusin β, were important mediators in arterial medial calcification (AMC) under CKD conditions. Salusin α could attenuate AMC and counteract the promoting effect of salusin β on AMC by inhibiting ERK activation and oxidative stress, and the inhibition of ERK activation effectively relieved AMC in CKD. Our findings provide new insights for preventing AMC under CKD condition.