Kynurenine 3-monooxygenase (KMO) is a critical regulator of renal ischemia-reperfusion injury

Abstract

Acute kidney injury (AKI) following ischemia-reperfusion injury (IRI) has a high mortality and lacks specific therapies. Here, we report that mice lacking kynurenine 3-monooxygenase (KMO) activity (Kmonull mice) are protected against AKI after renal IRI. This advances our previous work showing that KMO blockade protects against acute lung injury and AKI in experimental multiple organ failure caused by acute pancreatitis. We show that KMO is highly expressed in the kidney and exerts major metabolic control over the biologically-active kynurenine metabolites 3-hydroxykynurenine, kynurenic acid and downstream metabolites. In experimental AKI induced by unilateral kidney IRI, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared to wild-type (Kmowt) control mice. Together, these data confirm that flux through KMO contributes to AKI after IRI, and supports the rationale for KMO inhibition as a therapeutic strategy to protect against AKI during critical illness.