Kynurenine 3-monooxygenase 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 (Kmo^null mice) are protected against AKI after renal IRI. 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 kidney IRI, Kmo^null mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with wild-type (Kmo^wt) 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.

Kidney disease: drug target for acute injury following reperfusion

Inhibition of a metabolic enzyme linked to inflammation could be a novel treatment approach for sudden kidney failure following a “reperfusion” injury caused by blood flow returning to the organ after a period of insufficient blood supply. Damian Mole and colleagues from the University of Edinburgh, UK, temporarily blocked blood vessels leading to the kidneys of mice to induce organ damage. Mice that lacked a working copy of kynurenine 3-monooxygenase (KMO), a gene that encodes an enzyme involved in metabolizing an essential amino acid linked to immune activation, were protected from injury. These KMO-mutant mice experienced less damage to the kidney’s tubular cells and had fewer pro-inflammatory cells than genetically normal animals. The findings support the idea that blocking KMO and its associated metabolic pathway could help mitigate kidney damage following reperfusion injury in humans.