Salt Inducible Kinase (SIK): A potential intracellular signal involved in DOCA‐salt induced hypertension?

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Sodium sensitizes the cardiovascular‐renal axis resulting in salt‐sensitive hypertension, renal injury, and inappropriate activation of the renin‐angiotensin system (RAS). However, the molecular mechanisms and influences of sodium on blood pressure (BP) remain unclear. In the present study, we aimed to determine the unique effects of Na+ on renal function and the intracellular signaling involved in a rat model of DOCA‐salt induced hypertension. Adult Wistar male rats were subjected to left uninephrectomy, followed by SC administration of deoxycorticosterone acetate (DOCA; 8 mg/kg) or vehicle (mineral oil) and either normal or high salt diet (HS, 4% NaCl) in four groups, as follows: CTRL, CTRL/Salt, DOCA and DOCA/Salt (n=15, each group). CTRL and CTRL/Salt rats exhibited normal systolic BP. In CTRL/Salt rats, GFR was normal, despite BUN and proteinuria. Both, Na+ filtration and excretion loads increased from 0.23 ± 0.0074 in CTRL to 0.30 ± 0.011 (mEq) in CTRL/Salt and from 6.6 × 10−4 ± 1.5 × 10−4 in CTRL to 0.0095 ± 1.5 × 10−4 (mEq) in CTRL/Salt, (P<0.05), respectively. In addition, FENa increased 10 times, as Na+ reabsorption load (mEq) from 0.22 ± 0.064 in CTRL to 0.29 ± 0.011 in CTRL/Salt rats. Na+ reabsorption was increased two‐fold and in parallel with the Na,K‐ATPase activity in the renal cortex. In the hypertensive DOCA rats, these functions were preserved. DOCA/Salt rats showed exacerbated hypertension, increased FENa to a similar extent than CTRL/Salt rats along with augmentation of BUN, and proteinuria. In these rats, the high salt intake lead to 45% reduction in Na,K‐ATPase activity in renal cortex. The histological analyses revealed the presence of renal inflammation in DOCA and DOCA/Salt rats. High‐salt diet and DOCA increased sodium‐inducible kinase (SIK) immunoexpression in the glomeruli. These data suggest that in the absence of high BP, sodium contributes to increase Na,K‐ATPase activity and kidney injury without glomerular function alterations. However, in the DOCA/Salt rat model with established hypertension, increases in sodium excretion include alterations in Na,K‐ATPase activity and SIK, which are potential molecular intracellular signal involved in DOCA‐salt induced hypertension.Support or Funding InformationCNPq (420584/2013‐7 Science Without Borders grant, Government of Brazil)and NIH‐NIDDK (RO1DK104375)