Treatment with YKL-05-099, a salt inducible kinase (SIK) inhibitor, attenuates salt-sensitive hypertension: The molecular outcomes of SIK in the kidney

Abstract

Salt-inducible kinase (SIK) is a serine/threonine kinase that acts as an intracellular Na⁺ sensor, playing a role in salt-sensitive hypertension. We aimed to evaluate the therapeutic potential of YKL-05-099, a selective SIK inhibitor, in protecting kidney function and attenuating salt-sensitive hypertension. Male adult C57BL/6 J mice were randomly assigned to either a normal sodium (0.5 % NaCl; NS) or high‑sodium diet (4 % NaCl; HS) and further divided into two subgroups – receiving either intraperitoneal injection of saline or SIK inhibitor (SIKi; YKL-05-099, 20 mg/Kg/day). Blood pressure was measured by radiotelemetry for 15 days. On days 7 and 14, mice were placed in metabolic cages for 24 h urine collection. At the end of the treatment, blood and kidneys were collected for renal function assessment, and the renal cortex was extracted for biochemical analysis. HS intake led to a salt-sensitive hypertension model, as seen by increased systolic blood pressure (SPB), kidney damage and impairment in renal function. In the HS, SIKi treatment blocked the elevated SIK activity in the renal cortex, preventing kidney damage, proteinuria, and increased SBP. The Na⁺ balance was positive due, partly, to a higher (Na⁺+K⁺)-ATPase activity in the HS. SIKi treatment exerted an anti-inflammatory effect by attenuating HS-dependent macrophage infiltration and ROS production and decreasing the metalloprotease activity. Consequently, the kidney damage biomarker monocyte chemotactic protein type 1 excretion was enhanced. In conclusion, SIK inhibition rescued HS mice from salt-sensitive hypertension and kidney insufficiency by blocking inflammation, metalloprotease activity, and oxidative stress.

Significance

Salt-sensitive hypertension is a major contributor to chronic kidney disease and cardiovascular morbidity worldwide. Despite its prevalence, the underlying mechanisms linking high salt intake to renal injury remain incompletely understood, and targeted therapies are lacking. This study identifies salt-inducible kinase (SIK) as a key mediator of salt-induced renal dysfunction and systemic hypertension. By using a selective SIK inhibitor (YKL-05-099), we demonstrate that pharmacological inhibition of SIK effectively prevents kidney damage, inflammation, oxidative stress, and high blood pressure in a preclinical model of salt-sensitive hypertension. These findings highlight SIK as a promising therapeutic target for preserving renal function and managing salt-induced hypertension, paving the way for novel interventions in salt-related cardiovascular and renal diseases.