Abstract
Sodium thiosulfate (STS), a precursor of hydrogen sulfide (H(2)S), has demonstrated antihypertensive properties. Previous studies have suggested that H(2)S-based interventions can prevent hypertension in pediatric chronic kidney disease (CKD). However, the clinical application of STS is limited by its rapid release and intravenous administration. To address this, we developed a poly-lactic acid (PLA)-based nanoparticle system for sustained STS delivery and investigated whether weekly treatment with STS-loaded nanoparticles (NPs) could protect against hypertension in a juvenile CKD rat model. Male Sprague Dawley rats, aged three weeks, were fed a diet containing 0.5% adenine for three weeks to induce a model of pediatric CKD. STS-loaded NPs (25 mg/kg) were administered intravenously during weeks 6, 7, and 8, and at week 9, all rats were sacrificed. Treatment with STS-loaded NPs reduced systolic and diastolic blood pressure by 10 mm Hg and 8 mm Hg, respectively, in juvenile CKD rats. The protective effect of STS-loaded NPs was linked to increased renal expression of H(2)S-producing enzymes, including cystathionine γ-lyase (CSE) and D-amino acid oxidase (DAO). Additionally, STS-loaded NP therapy restored nitric oxide (NO) signaling, increasing L-arginine levels, which were disrupted in CKD. Furthermore, the beneficial effects of STS-loaded NPs were associated with inhibition of the renin-angiotensin system (RAS) and the enhancement of the NO signaling pathway. Our findings suggest that STS-loaded NP treatment provides sustained STS delivery and effectively reduces hypertension in a juvenile CKD rat model, bringing us closer to the clinical translation of STS-based therapy for pediatric CKD-induced hypertension.