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. 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, Kmonull mice had preserved renal function, reduced renal tubular cell injury, and fewer infiltrating neutrophils compared with 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.
Highlights
In eukaryotes, the metabolic fate of the essential aminoacid tryptophan is conversion via the kynurenine pathway into a range of metabolites that includes kynurenic acid, 3hydroxykynurenine, and quinolinic acid
The kynurenine pathway diverges at kynurenine into two distinct branches that are regulated by kynurenine aminotransferases (KATs) and kynurenine 3-monooxygenase (KMO), respectively (Fig. 1)
To determine whether absent KMO activity affected the severity of Acute kidney injury (AKI) after ischemia–reperfusion injury (IRI), we compared the effect of experimental IRI in mice
Summary
The metabolic fate of the essential aminoacid tryptophan is conversion via the kynurenine pathway into a range of metabolites that includes kynurenic acid, 3hydroxykynurenine, and quinolinic acid. Enzymes involved in the metabolism of tryptophan along the kynurenine pathway are located throughout the body and brain, and are most abundant in the liver and kidney. The conversion of tryptophan to N-formylkynurenine (KYN) is catalyzed by tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenases (IDOs). The kynurenine pathway diverges at kynurenine into two distinct branches that are regulated by kynurenine aminotransferases (KATs) and kynurenine 3-monooxygenase (KMO), respectively (Fig. 1). KMO is the only route of 3-hydroxykynurenine production known to occur in humans. KMO localizes to the outer membrane of mitochondria, and is highly expressed in peripheral tissues, including liver and kidney[1]
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