Abstract P036: Salt-inducible Kinase (SIK): A Pharmacological Target Of Salt-sensitive Hypertension

Abstract

Salt-inducible kinase (SIK) is a serine/threonine kinase involved in intracellular sensing network. However, its role in the development of salt-sensitive hypertension remains uncertain. We used a mouse model of salt-sensitive hypertension to test the hypothesis that SIK inhibition decreases systolic blood pressure (SBP) and renal injury. Male C57BL/6J mice (20-25g) were randomly fed either normal salt (NS; 0.5% NaCl) or high salt (HS; 4% NaCl) diet and daily treated or not with a SIK inhibitor (iSIK, YKL-05-099, 20 mg/Kg, via IP; n=6/group; CEUA: 013/19). In these mice: 1) SBP was measured by telemetry for 15 days; 2) Urine metabolic collection for 24 h was performed on day 14; and 3) Blood and kidney samples were collected after euthanasia on day 15. HS diet increased SBP during both day and night times (Day: from 114±1 to 136±1 mmHg; Night: from 127±3 to 141±4 mmHg; p<0.0001). Treatment with iSIK prevented increases in SBP (Day: 112±1 and Night: 123±2 mmHg). iSIK did not change SBP nor renal Na + handling in NS diet. In HS mice, iSIK prevented the augmentation of urine osmolality (HS: 1692±14 vs. HS+iSIK: 1104±34 mOsm/Kg H 2 O; p=0.0019) but did not change increases in urine volume and Na + excretion neither decreases in urine creatinine. Moreover, HS mice displayed glomerular segmentation, tubular interstitial disruption, infiltration of inflammatory cells and collagen accumulation. These responses were attenuated by iSIK. Increased kidney SIK activity in HS mice were sensitive to iSIK (HS: 222.8±45 vs. HS+iSIK: 19.10±15 pmol.mg -1 .min -1 ; p=0.0026). The augmentation of (Na + +K + )ATPase activity in HS mice was exacerbated during iSIK (HS: 517±112 and HS+SIKi: 763±18 mmol.mg -1 ;.min -1 p<0.0001). Equally important, SIK inhibition in HS mice: 1) Decreased plasma MCP-1 levels (HS: 79±7 vs. HS+iSIK: 51±2 pg/dL; p=0.0019); 2) Prevented HS-dependent macrophages renal infiltration; 3) Decreased kidney ROS; and 4) Decreased kidney TGF-β protein expression (HS: 1.9±0.01 vs. HS+iSIK: 1.4±0.3 au. p=0.0007). Thus, the data indicate that SIK inhibition attenuates salt-sensitive hypertension and prevents kidney injury, without altering Na + handling in response to HS. In perspective, SIK might be a pharmacological target for salt-sensitive hypertension treatment.