Integrated spatial and functional metabolic profiling identified the thick ascending limb as a mitochondrial vulnerability hub in acute kidney injury

作者：Grégoire Arnoux, Justine Serre, Verissimo Thomas, Matthieu Tihy, Shawn M. Davidson, Sandrine Placier, Charles Verney, Sangla Frédéric, Paolucci Deborah, Marylise Fernandez, De Seigneux Sophie, Naesens Maarten, Juliette Hadchouel, Éric Feraille, Stellor Nlandu Khodo, Pierre Galichon, Legouis David · 发表于：Kidney International · 年份：2025 · DOI：10.1016/j.kint.2025.07.021 · 被引用次数：8 · 研究领域：Acute Kidney Injury Research、Cardiac Ischemia and Reperfusion、Renal and Vascular Pathologies

INTRODUCTION: Acute kidney injury (AKI) is a common complication in critically ill patients and often progresses to chronic kidney disease (CKD), increasing morbidity and mortality. Despite its clinical relevance, the metabolic mechanisms underlying kidney injury remain poorly understood. METHODS: To help define this, we used an integrated approach combining spatial and single-cell transcriptomics, immunofluorescence, and isotope tracing imaging to investigate the spatial distribution of kidney energy metabolism in murine models and in human kidney allografts following transplantation. RESULTS: The outer medullary thick ascending limb (TAL) was identified as the most metabolically active nephron segment, characterized by a high reliance on oxidative phosphorylation and fatty acid oxidation for ATP production. This metabolic profile renders TAL cells particularly vulnerable to injury, a finding confirmed in both murine and human models of AKI and CKD. We further examined the effect of propofol, a widely used sedative in critical care, on kidney metabolism. Propofol impaired oxidative phosphorylation, especially within the outer medulla, inducing a metabolic shift toward anaerobic glycolysis. In a murine ischemia-reperfusion model, propofol preconditioning exacerbated tubular injury in the outer medulla. In kidney transplant recipients, higher intraoperative exposure to propofol was associated with reduced oxidative metabolism, increased tubular injury and poorer long-term kidn...