The preferential injury of outer renal medulla after ischemia-reperfusion relies on high oxidative metabolism

Acute kidney injury (AKI) is a prevalent and significant complication in critically ill patients, and its management remains a considerable challenge. The kidney is a highly metabolic organ, consuming and producing substantial amounts of ATP, mainly through mitochondrial oxidative phosphorylation. Recently, mitochondrial dysfunction has been identified as a key factor in the pathophysiology of AKI and the progression to chronic kidney disease. The kidney is a complex organ, comprising millions of structural and functional units. These nephrons are composed of different cell types dwelling within specific metabolic microenvironment. Whether the metabolic spatialization in the kidney has consequences on tubular injury distribution and severity remains unclear. In this study, we identified the high metabolic rate of the outer stripe of the outer medulla (OSOM) and its substrate preference flexibility, relying on both glycolysis and fatty acid oxidation (FAO) to fulfill its ATP demands. We demonstrated that the OSOM is susceptible to mitochondrial and FAO impairment induced by propofol, the most used sedative in intensive care settings, which exacerbates tubular injury during AKI. In the clinical setting, the cumulative dose of propofol is positively correlated with oxidative metabolism disruption and histological and function outcomes in renal allograft recipients. Finally, we found that the loop of Henle, the OSOM major constituent, was the most injured segment during AKI in patients. This study shows how renal metabolic spatialization impacts tubular injury severity. We identified the OSOM as the most metabolically active and the most injured region of the kidney both in humans and mice. We demonstrated that propofol is a potent inhibitor of renal mitochondrial function and FAO exacerbating tubular injury in the OSOM upon IRI. Translational StatementO_LIAerobic metabolism is basally enhanced in the renal OSOM, including the S3 proximal tubule, the thick ascending limb of the loop of Henle and Distal Convoluted Tubule C_LIO_LIPT cells as well as TAL cells are significantly targeted by injury in human AKI. C_LIO_LIPropofol impairs renal mitochondrial function worsening tubular injury during ischemia reperfusion. C_LI