Antagonistic modulation of SIK1 and SIK2 isoforms in high blood pressure and cardiac hypertrophy triggered by high-salt intake

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.

KEYWORDS:

• Salt inducible kinase 1 (SIK1)
• salt inducible kinase 2 (SIK2)
• SIK1 knockout mouse
• SIK2 knockout mouse
• blood pressure
• high-salt intake
• left ventricle hypertrophy

Authorship contributions

NMP, BI and PSS participated in research design, performed data analysis and wrote or contributed to the writing of the manuscript. NMP and BI conducted experiments. All authors have contributed to the discussion of the results and have approved the final manuscript.

Declaration of competing interest

NMP, BI and PSS were employees of BIAL at the time of the studies.

Additional information

Funding

We thank BIAL-Portela & Cª, S.A. for providing animals, reagents and technical support. This work was supported in part by Foundation for Science and Technology (FCT – Portugal, COMPETE/FEDER Grants [PTDC/DTP-FTO/0735/2014 and UID/BIM/4308/2016]).