ABSTRACT

Salt-inducible kinases (SIKs) represent a subfamily of AMPK family kinases. SIK1 has been shown to act as a mediator during the cellular adaptation to variations in intracellular sodium in a variety of cell types. SIK2, as an isoform of the SIK family, modulates various biological functions and acts as a signal transmitter in various pathways. To evaluate the role of both SIK1 and SIK2 isoforms in blood pressure (BP), body fluid regulation and cardiac hypertrophy development, we made use of constitutive sik1^-/- (SIK1-KO), sik2^-/- (SIK2-KO), double sik1^-/-sik2^-/- (double SIK1*2-KO) knockout and wild-type (WT) mice challenged to a standard (0.3% NaCl) or chronic high-salt (HS, 8% NaCl) diet intake for 12 weeks.

Mice, under a standard diet intake, had similar and normal BP. On a chronic HS intake, SIK1-KO and double SIK1*2-KO mice showed increased BP, but not WT and SIK2-KO mice. A chronic HS intake led to the development of cardiac left ventricle hypertrophy (LVH) in normotensive WT and hypertensive SIK1-KO mice, but not in SIK2-KO mice. Double SIK1*2-KO mice under standard diet intake show normal BP but an increased LV mass. Remarkably, in response to a dietary stress condition, there is an increase in BP but LVH remained unchanged in double SIK1*2-KO mice.

In summary, SIK1 isoform is required for maintaining normal BP in response to HS intake. LVH triggered by HS intake requires SIK2 isoform and is independent of high BP.

 抽象的

盐诱导激酶 (SIK) 代表 AMPK 家族激酶的一个亚家族。 SIK1 已被证明在多种细胞类型的细胞适应细胞内钠变化的过程中充当介质。 SIK2作为SIK家族的同种型，调节多种生物功能并在多种途径中充当信号传递者。为了评估 SIK1 和 SIK2 亚型在血压 (BP)、体液调节和心脏肥大发展中的作用，我们利用了组成型sik1 ^-/- (SIK1-KO)、 sik2 ^-/- (SIK2-KO)、双sik1 ^-/- sik2 ^-/- (双 SIK1*2-KO) 敲除小鼠和野生型 (WT) 小鼠接受标准 (0.3% NaCl) 或慢性高盐 (HS, 8% NaCl) 饮食摄入的挑战12周。

在标准饮食摄入下，小鼠的血压相似且正常。在长期摄入 HS 时，SIK1-KO 和双 SIK1*2-KO 小鼠表现出血压升高，但 WT 和 SIK2-KO 小鼠则没有。长期摄入 HS 会导致血压正常的 WT 和高血压 SIK1-KO 小鼠出现心脏左心室肥大 (LVH)，但 SIK2-KO 小鼠则不会。标准饮食摄入下的双 SIK1*2-KO 小鼠血压正常，但左心室质量增加。值得注意的是，在双 SIK1*2-KO 小鼠中，为了应对饮食应激条件，血压升高，但 LVH 保持不变。

总之，SIK1 异构体是维持正常血压以响应 HS 摄入所必需的。 HS 摄入引发的 LVH 需要 SIK2 同工型，并且与高血压无关。