Sepsis causes a dysregulated host response to infection and frequently leads to sepsis‑associated acute kidney injury (SA‑AKI). The eicosanoid 20‑hydroxyeicosatetraenoic acid (20‑HETE) is a known regulator of vascular tone. The authors investigated whether disruption of 20‑HETE signaling via the receptor GPR75 contributes to septic renal dysfunction and whether restoration of this pathway could improve systemic and renal hemodynamics and attenuate kidney injury.
The preclinical component used a cecal ligation and puncture (CLP) model in Sprague‑Dawley rats to induce sepsis and SA‑AKI. Cardiac and renal ultrasonographic measurements were performed to assess hemodynamic status. Blood samples were collected for biochemical assessment of renal function and quantification of circulating 20‑HETE. Kidney tissues were harvested to evaluate components of the 20‑HETE–GPR75–PLC/PKC signaling cascade and for histological assessment with hematoxylin and eosin staining. The authors also tested a pharmacological 20‑HETE analog and assessed the effects of PKC inhibition on the analog’s protective actions.
CLP‑induced sepsis produced a biphasic hemodynamic course in the animal model. An early compensatory phase was followed by a later decompensated cardiovascular state. This progression was accompanied by deteriorating renal function and evidence of tubular injury on histology. Ultrasonographic parameters were used to monitor systemic and renal hemodynamic changes over the course of sepsis in the animals.
Septic animals exhibited progressive depletion of circulating and renal 20‑HETE and reduced expression of renal GPR75. The study evaluated downstream signaling components and implicated the PLC/PKC pathway as a mediator of 20‑HETE–GPR75 effects in kidney tissue. Biochemical markers of renal dysfunction, including serum creatinine and blood urea nitrogen (BUN), worsened in parallel with these molecular changes.
Administration of a 20‑HETE analog to septic rats restored aspects of systemic and renal hemodynamics. Treated animals showed increased mean arterial pressure and reduced serum creatinine and BUN compared with untreated septic controls. Renal histology improved after analog treatment, with attenuation of tubular injury. When PKC was inhibited pharmacologically, the protective effects of the 20‑HETE analog were partially attenuated, supporting a role for PKC‑dependent signaling downstream of GPR75 in mediating renal protection.
In a clinical component, the authors measured circulating 20‑HETE concentrations and derived renal hemodynamic parameters using point‑of‑care ultrasound in healthy individuals and patients with sepsis. Circulating 20‑HETE concentrations were lower in patients with sepsis than in healthy controls and were lowest among patients who developed SA‑AKI. These reductions paralleled changes in renal hemodynamic parameters observed by ultrasound.
Across the translational experiments, depletion of 20‑HETE and reduced renal GPR75 expression were temporally associated with impaired systemic and renal hemodynamic regulation and the development of renal dysfunction and tubular injury in sepsis. Restoration of 20‑HETE signaling improved mean arterial pressure, lowered serum creatinine and BUN, and ameliorated histological injury in septic rats. Partial reversal of benefit by PKC inhibition implicates PLC/PKC signaling in the mechanism. Clinical observations in septic patients mirrored the preclinical findings, with lower circulating 20‑HETE in sepsis and the lowest levels in SA‑AKI.
The study links sepsis‑associated depletion of 20‑HETE and downregulation of GPR75 with impaired renal hemodynamic adaptation and the development of SA‑AKI. Restoration of 20‑HETE signaling in the animal model improved systemic and renal hemodynamics and reduced biochemical and histologic markers of kidney injury, with evidence that PLC/PKC‑dependent signaling contributes to these effects. The parallel reduction of circulating 20‑HETE in patients with sepsis and SA‑AKI suggests translational relevance and raises the possibility that targeting the 20‑HETE–GPR75 axis could be explored as a therapeutic strategy to preserve renal perfusion and limit SA‑AKI.
This article is a preprint and has not undergone peer review. The source reports the experimental approaches and outcomes but exact methodological details such as dosing regimens, sample sizes, statistical analyses, and safety assessments were described in the full manuscript; readers should consult the original preprint for those specifics. Because the work is not yet peer‑reviewed, findings should be considered provisional pending external validation and replication.