Question:

The serum- and glucocorticoid-inducible kinase Sgk1 plays a role in cardiac remodeling and development of heart failure, which is paralelled by Sgk1 dependent stimulation of the cardiac sodium/hydrogen exchanger Nhe1. Glucocorticoids stimulate Sgk1 expression and foster cardiac remodeling. The present study thus explored whether the glucocorticoid dexamethasone influenced cardiac Sgk1 dependent mechanisms.

Methods:

Experiments were performed in HL-1 cardiomyocytes, in gene targeted mice lacking functional Sgk1 (sgk1-/-) and in wild type mice (sgk1+/+). Gene expression was determined using quantitative RT-PCR, Nhe1 phosphorylation in Nhe1 immunoprecipitated cardiac tissue samples, and Nhe activity from Na⁺-dependent realkalinization after an ammonium pulse.

Results:

Treatment of HL-1 cardiomyocytes with dexamethasone significantly increased Sgk1, Nhe1 and Spp1 mRNA expression and Nhe activity, effects blunted by cotreatment of HL-1 cardiomyocytes with the Sgk1 inhibitor EMD638683. The Nhe1 inhibitor cariporide prevented dexamethasone stimulated Spp1 mRNA expression. In vivo, dexamethasone significantly increased cardiac Sgk1 mRNA levels in wild type mice. Dexamethasone further significantly increased cardiac Nhe1 mRNA expression and Nhe1 phosphorylation at Ser⁷⁰³ which represents a putative phosphorylation site recognition motif for Sgk1 and is important for Nhe1 activation. All effects of dexamethasone were strongly reduced in sgk1-/- mice. Furthermore, cardiac Spp1, Ctgf, Nppa and Nppb mRNA levels were significantly increased in dexamethasone treated wild type mice, an effect significantly blunted in sgk1-/- mice.

Conclusions:

Sgk1 is involved in cardiac effects of glucocorticoids, and participates in the phosphorylation and activation of the cardiac sodium hydrogen exchanger.