Effect of fenofibrate and gemfibrozil on kynurenic acid production in rat kidney in vitro: old drugs, new possibilities

Abstract

Abstract Kidney dysfunction significantly increases cardiovascular risk, even in the setting of minor function decline. Hypertriglyceridemia is the most common finding among lipid abnormalities in patients with kidney disorders. PPARα (peroxisome proliferator-activated receptor-α) agonists called fibrates are main agents used to lower triglycerides level. Kynurenic acid (KYNA) is one of tryptophan (Trp) metabolites, directly formed from L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). KAT I and KAT II are the best studied KAT isoenzymes. KYNA is classified as a uremic toxin, which level correlates with kidney function decline. High fat diet, known as ketogenic diet, was previously shown to increase KYNA concentration. Purpose: The aim of this study was to analyze the effect of most commonly used fibrates, fenofibrate and gemfibrozil, on KYNA production and KATs activity in rat kidney in vitro. Methods: The influence of fenofibrate and gemfibrozil on KYNA synthesis, as well as both KATs activity, was tested in rat kidney homogenates in vitro after 2 hours incubation in the presence of KYNA precursor and selected drug. Each drug was examined at increasing concentrations up to 1 mM. KYNA formation was analyzed through high performance liquid chromatography (HPLC). Results: Fenofibrate and gemfibrozil significantly decreased KYNA synthesis and both KATs activity in rat kidney in vitro. Conclusion: Fenofibrate and gemfibrozil decrease KYNA production in rat kidney in vitro through inhibition of KAT I and KAT II isoenzymes. Presented results show novel mechanism of fibrates action in the kidney, indicating potential role of examined drugs in kidney function regulation.