Work

Urolithin A preserves renal perfusion and function and attenuates inflammasome-associated signaling in a translational porcine model of sepsis-induced acute kidney injury

Year: 2026

Type: preprint

Abstract: Sepsis-associated acute kidney injury (SA-AKI) is a major complication of critical illness for which no targeted therapy is available. Urolithin A (UA), a gut microbiota-derived metabolite with anti-inflammatory and antioxidant properties, has shown organ-protective effects in preclinical studies, but its effects on renal physiology during sepsis remain unknown. We evaluated UA in a translational porcine model of autologous fecal peritonitis-induced sepsis using 6–8-week-old male Landrace × Large White crossbred pigs. Animals were assigned to sham, fecal peritonitis (FP), or FP plus intravenous UA administered after sepsis induction. At 24 hours, systemic and renal hemodynamics, glomerular filtration rate (GFR), kidney injury biomarkers, inflammatory and oxidative stress indices, and renal inflammasome-associated proteins were assessed. Complementary studies used lipopolysaccharide-challenged primary porcine proximal tubular epithelial cells. FP produced a hypodynamic septic phenotype with systemic and renal hypoperfusion, increased renal vascular resistance, decreased GFR, and increased kidney injury biomarkers. UA attenuated hemodynamic abnormalities, preserved GFR, and reduced kidney injury, inflammation, and oxidative stress. FP increased renal immunoreactivity for NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), cleaved caspase-1, gasdermin D N-terminal fragment, interleukin-1β, and interleukin-18; these responses were attenuated by UA. In porcine proximal tubular cells, UA reduced LPS-induced caspase-1 activity and expression of NLRP3, cleaved caspase-1, and gasdermin D N-terminal fragment. These findings demonstrate renal physiological protection by UA in a large-animal model of polymicrobial sepsis and support further evaluation of UA as an adjunctive intervention for SA-AKI.

Source: Research Square

DOI: 10.21203/rs.3.rs-10630708/v1

Authors: Julia de la Cruz, Olugbenga Michael, Praghalathan Kanthakumar, Adebowale Adebiyi

Institution: University of Missouri

Language: English

Topic: Acute Kidney Injury Research

Subfield: Nephrology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

Funders: American Heart Association, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases