Loss of 20-HETE-GPR75 Signaling Impairs Renal Hemodynamic Adaptation in Sepsis

Abstract

BACKGROUD: Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. It frequently precipitates sepsis-associated acute kidney injury (SA-AKI). 20-Hydroxyeicosatetraenoic acid (20-HETE), is an important regulator of vascular tone. We aim to investigate whether disruption of 20-HETE signaling contributes to septic renal dysfunction. METHODS: In the animal study, Sprague-Dawley rats underwent the cecal ligation and puncture to induce sepsis and SA-AKI. Comprehensive cardiac and renal ultrasonographic assessments were performed in all animals. Blood samples were collected for biochemical assessment of renal function and quantification of circulating 20-HETE levels. Kidney tissues were harvested for analysis of the 20-HETE-GPR75-PLC/PKC signaling pathway and histological evaluation by hematoxylin and eosin staining. In the clinical study, circulating 20-HETE levels and renal hemodynamic parameters derived from point-of-care ultrasound were evaluated in healthy individuals and patients with sepsis. Venous blood samples were collected for quantification of serum 20-HETE concentrations. RESULTS: Firstly, CLP-induced septic rats produced a biphasic hemodynamic response, with early compensation followed by late cardiovascular decompensation, accompanied by progressive renal dysfunction, tubular injury, depletion of circulating and renal 20-HETE, and reduced renal GPR75 expression. Secondly, Restoration of 20-HETE signaling with a pharmacological analog improved systemic and renal hemodynamics, increased MAP, reduced serum creatinine, blood urea nitrogen, and ameliorated renal pathological injury. These protective effects were partially attenuated by PKC inhibition, implicating PKC-dependent signaling in 20-HETE-mediated renal protection. Moreover, in septic patients, circulating 20-HETE concentrations were reduced compared with healthy individuals and were lowest among those with SA-AKI, paralleling alterations in renal hemodynamic parameters measured by point-of-care ultrasound. CONCLUSIONS: Sepsis-associated depletion of 20-HETE accompanies impaired systemic and renal hemodynamic regulation and is associated with the development of SA-AKI. Restoration of 20-HETE signaling improves hemodynamic function and attenuates renal injury, potentially involving GPR75-associated PLC/PKC signaling. KEY WORDS: sepsis-associated acute kidney injury, 20-hydroxyeicosatetraenoic acid, GPR75, renal hemodynamics, point-of-care ultrasonography