The Triad Na Activated Na Channel (Nax)-Salt Inducible KINASE (SIK) and (Na + K)-ATPase: Targeting the Villains to Treat Salt Resistant and Sensitive Hypertension

The Na-activated Na channel (Nax) and salt-inducible kinase (SIK) are stimulated by increases in local Na concentration, affecting (Na + K)-ATPase activity. To test the hypothesis that the triad Nax/SIK/(Na + K)-ATPase contributes to kidney injury and salt-sensitive hypertension (HTN), uninephrectomized male Wistar rats (200 g; = 20) were randomly divided into 4 groups based on a salt diet (normal salt diet; NSD-0.5% NaCl-or high-salt diet; HSD-4% NaCl) and subcutaneous administration of saline (0.9% NaCl) or deoxycorticosterone acetate (DOCA, 8 mg/kg), as follows: Control (CTRL), CTRL-Salt, DOCA, and DOCA-Salt, respectively. After 28 days, the following were measured: kidney function, blood pressure, (Na + K)-ATPase and SIK1 kidney activities, and Nax and SIK1 renal expression levels. SIK isoforms in kidneys of CTRL rats were present in the glomerulus and tubular epithelia; they were not altered by HSD and/or HTN. CTRL-Salt rats remained normotensive but presented slight kidney function decay. HSD rats displayed augmentation of the Nax/SIK/(Na + K)-ATPase pathway. HTN, kidney injury, and kidney function decay were present in all DOCA rats; these were aggravated by HSD. DOCA rats presented unaltered (Na + K)-ATPase activity, diminished total SIK activity, and augmented SIK1 and Nax content in the kidney cortex. DOCA-Salt rats expressed SIK1 activity and downregulation in (Na + K)-ATPase activity in the kidney cortex despite augmented Nax content. The data of this study indicate that the (Na + K)-ATPase activity response to SIK is attenuated in rats under HSD, independent of HTN, as a mechanism contributing to kidney injury and salt-sensitive HTN.