Kynurenine Pathway Dysregulation Impairs Podocyte Morphology and Bioenergetics In Vitro and Leads to Glomerular Dysfunction

Managing tryptophan (TRP) availability is important for cell homeostasis, and a dynamic balance between dietary intake and its catabolism is crucial. The enzymes of the kynurenine pathway (KP) mediate the main catabolic route for TRP. Its intermediary products, collectively known as kynurenines, are considered metabolically active and highly pleiotropic. Some progress has been made in the description of the biological function of the kynurenines, and despite the growing number of studies that show an association between TRP metabolism and kidney function, not much is known about the cellular mechanisms involved. To assess if the kynurenines play a role in glomerular dysfunction, we carried out a series of experiments aimed at describing the effect of changes in the relative abundance of the kynurenines on cells of the glomerulus, both in vivo and in vitro. We used a transgenic zebrafish line as a model to show that systemic changes in the KP either by morpholino knockdown, enzymatic inhibition, or kynurenine supplementation, lead to pericardial effusion, yolk sac edema, and excretion of high molecular weight proteins, all signs of impaired glomerular filtration. Cultured podocytes incubated with a KP inhibitor show changes in cell size, morphology and focal adhesions, leading to a higher detachment rate. Additionally, there is a change in the polarization status of the mitochondria, showing a loss of membrane potential and an alteration of bioenergetics parameters. Taken together, our results highlight the importance of kynurenine metabolite levels in the maintenance of a functioning filtration barrier.