Possible role of brain salt-inducible kinase 1 in responses to central sodium in Dahl rats

Abstract

In Dahl salt-sensitive (S) rats, Na+ entry into the cerebrospinal fluid (CSF) and sympathoexcitatory and pressor responses to CSF Na+ are enhanced. Salt-inducible kinase 1 (SIK1) increases Na+/K+-ATPase activity in kidney cells. We tested the possible role of SIK1 in regulation of CSF [Na+] and responses to Na+ in the brain. SIK1 protein and activity were lower in hypothalamic tissue of Dahl S (SS/Mcw) compared with salt-resistant SS.BN13 rats. Intracerebroventricular infusion of the protein kinase inhibitor staurosporine at 25 ng/day, to inhibit SIK1 further increased mean arterial pressure (MAP) and HR but did not affect the increase in CSF [Na+] or hypothalamic aldosterone in Dahl S on a high-salt diet. Intracerebroventricular infusion of Na+-rich artificial CSF caused significantly larger increases in renal sympathetic nerve activity, MAP, and HR in Dahl S vs. SS.BN13 or Wistar rats on a normal-salt diet. Intracerebroventricular injection of 5 ng staurosporine enhanced these responses, but the enhancement in Dahl S rats was only one-third that in SS.BN13 and Wistar rats. Staurosporine had no effect on MAP and HR responses to intracerebroventricular ANG II or carbachol, whereas the specific protein kinase C inhibitor GF109203X inhibited pressor responses to intracerebroventricular Na+-rich artificial CSF or ANG II. These results suggest that the SIK1-Na+/K+-ATPase network in neurons acts to attenuate sympathoexcitatory and pressor responses to increases in brain [Na+]. The lower hypothalamic SIK1 activity and smaller effect of staurosporine in Dahl S rats suggest that impaired activation of neuronal SIK1 by Na+ may contribute to their enhanced central responses to sodium.