S1PR3 antagonism ameliorates endothelial dysfunction in septic acute kidney injury through the ROCK1-Drp1 signalling...

Sphingosine-1-phosphate receptor 3 (S1PR3) is predominantly expressed in endothelial cells and plays important roles in inflammatory responses. However, its contribution to the pathogenesis of septic acute kidney injury (S-AKI) remains poorly defined. This study aimed to elucidate the role and underlying mechanisms of S1PR3 in endothelial dysfunction during S-AKI.

S-AKI was induced in mice by intraperitoneal lipopolysaccharide (LPS) injection. Renal endothelial function and mitochondrial integrity were assessed by flow cytometry, Evans blue dye (EBD) assays and transmission electron microscope (TEM). Mechanistic studies were conducted in human umbilical vein endothelial cells (HUVECs) using the S1PR3 antagonist TY-52156 and liposomal formulations.

Serum creatinine (SCr), blood urea nitrogen (BUN) and renal S1PR3 expression were significantly increased 24 h after LPS challenge in wild-type mice, with S1PR3 predominantly localised to endothelial cells. Compared with S1pr3^+ /+ mice, S1pr3^-/- mice exhibited improved renal function, reduced leukocyte infiltration and enhanced ATP production. S1PR3 activation was associated with mitochondrial dysfunction, cytoskeletal remodelling and increased endothelial permeability. In vitro, TY-52156 reduced mitochondrial Ca²⁺ accumulation, restored ATP levels and preserved cytoskeletal organisation and adherens junction integrity. To improve solubility and biocompatibility, TY-52156 was encapsulated into negatively or neutrally charged liposomes, of which LP-Neg-TY-52156 showed superior efficacy. In vivo, LP-Neg-TY-52156 alleviated endothelial leakage, mitochondrial injury and renal dysfunction in S-AKI.

Endothelial S1PR3 is a key mediator of mitochondrial dysfunction and barrier disruption in S-AKI. Liposomal delivery of S1PR3 antagonists represents a promising therapeutic strategy for preserving endothelial integrity and attenuating septic renal injury.