The influence of cyclooxygenase inhibitors on kynurenic acid production in rat kidney: a novel path for kidney protection?

BACKGROUND: Kidney diseases have become a global health problem, affecting about 15% of adults and being often under-recognized. Immunological system activation was shown to accelerate kidney damage even in inherited disorders. The kynurenine pathway is the main route of tryptophan degradation. A metabolite of kynurenine (KYN), kynurenic acid (KYNA), produced by kynurenine aminotransferases (KATs), was reported to affect fluid and electrolyte balance as a result of natriuresis induction. The accumulation of KYNA was shown in patients with impaired kidney function and its level was related to the degree of kidney damage. Cyclooxygenase (COX) inhibitors are well-known analgesics and most of them demonstrate an anti-inflammatory effect. Their main mechanism of action is prostaglandin synthesis blockade, which is also responsible for their nephrotoxic potential. Since the KYN pathway is known to remain under immunological system control, the purpose of this study was to analyze the effect of 9 COX inhibitors on KYNA production together with KATs’ activity in rat kidneys in vitro. METHODS: Experiments were carried out on kidney homogenates in the presence of L-KYN and the selected compound in 6 various concentrations. RESULTS: Among the examined COX inhibitors only acetaminophen did not change KYNA production in rat kidneys in vitro. Additionally, acetaminophen did not affect the activity of KAT I and KAT II, whereas acetylsalicylic acid and ibuprofen inhibited only KAT II. The remaining COX inhibitors decreased the activity of both KATs in rat kidneys in vitro. CONCLUSION: Our study provides novel mechanisms of COX inhibitors action in the kidney, with possible implications for the treatment of kidney diseases. GRAPHICAL ABSTRACT: [Image: see text]