Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)
Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased Na+,K+-ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 (TGFβ1)signaling and down-regulation of SIK1 induces the expression of extracellular matrix remodeling genes.
Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and/or function of the vasculature, leading to higher blood pressure.
Methods and Results: SIK1 knockout (sik1-/-) and wild-type (sik1+/+) mice were challenged to a normal- or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1-/- mice showed increased collagen deposition in the aorta but similar blood pressure compared to the sik1+/+ mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1-/- mice exhibited up-regulated TGFβ1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced up-regulation of collagen in aortic adventitial fibroblasts, and enhanced the expression of contractile markers and of endothelin-1 in VSMCs.
Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via TGFβ1-signaling inhibition.
- salt-induced hypertension
- contractile smooth muscle cell phenotype
- salt sensitivity hypertension
- salt intake
- vascular remodeling
- vascular smooth muscle
- Received June 3, 2014.
- Revision received December 30, 2014.
- Accepted December 31, 2014.