Kynurenine Pathway in Chronic Kidney Disease: What's Old, What's New, and What's Next?

Abstract

Impaired kidney function and increased inflammatory process occurring in the course of Chronic Kidney Disease (CKD) contribute to the development of complex amino-acid alterations. The essential amino-acid tryptophan (TRP) undergoes extensive metabolism along several pathways, resulting in the production of many biologically active compounds. The results of many studies have shown that its metabolism via the kynurenine pathway is potently increased in the course of CKD. Metabolites of this pathway exhibit differential, sometimes opposite, roles in several biological processes. Their accumulation in the course of CKD may induce oxidative cell damage which stimulates inflammatory processes. They can also modulate the activity of numerous cellular signaling pathways through activation of the aryl hydrocarbon receptor, leading to the disruption of homeostasis of various organs. As a result, they can contribute to the development of the systemic disorders accompanying the course of chronic renal failure. This review gathers and systematizes reports concerning the knowledge connecting the kynurenine pathway metabolites to systemic disorders accompanying the development of CKD.

Keywords: Tryptophan; chronic kidney disease; kynurenine; mineral and bone disorders; neurological disorders; thrombosis.

Figure 1.

Mechanisms of peripheral kynurenines promoting vasodilatation and thrombosis. Kynurenine pathway metabolites can be involved in the development of thrombosis by deregulation of plasma coagulation factors, induction of endothelial cell dysfunction, and stimulating cell TF overexpression, through AhR-pathway. The up-regulation of IDO in coronary atherosclerotic plaques in combination with the increasing level of inflammatory factors leads to the increased oxidative stress level and the AhR pathway stimulation. It might contribute to thrombus formation through TF upregulation in activated macrophages. Parallel the increase in KYN and KYNA concentration in endothelial cells induce arterial relaxation by activation of the adenylate cyclase and soluble guanylate cyclase pathways. It indicates that the activation of the kynurenine pathway may also represent a local compensatory mechanism counteracting hypertension the increase in blood pressure. Abbreviations: AhR, Aryl hydrocarbon receptor; CCL2, Chemokine (C-C motif) ligand 2; CCL4, Chemokine (C-C motif) ligand 4; GFR, Glomerular filtration rate; IDO, 2,3-indole dioxygenase; INF-γ, Interferon gamma; KYN, Kynurenine; KYNA, Kynurenic acid; LP, Lipopolysaccharide; NO, nitric oxide; ROS, Reactive oxygen species; sICAM-1, Soluble intercellular adhesion molecule-1; TF, Cell tissue factor; TNF-α, Tumor necrosis factor alpha; TRP, Tryptophan; sVCAM-1, Soluble circulating vascular cell adhesion molecule-1; vWF, von Willebrand factor.

Figure 2.

Mechanisms of peripheral kynurenines promoting bone fractures. The effect of circulating kynurenine pathway metabolites on bone tissue may be explained by their interaction with a cytosolic receptor AhR. Its activation may lead to unfavorable changes in bone metabolism through induction of CYP1A1 transcription and activation of the CYP1A1-dependent pathway. In turn, stimulation of the AhR in osteoblasts, through the CYP1A1 pathway stimulation, leads to the inhibition of proliferation and differentiation of osteoblasts in a collagen-induced arthritis mouse model by activating the signalling pathway dependent on extracellular signal-regulated kinases. At the same time, the activation of CYP1A1 in osteoclasts leads to an increase in their activity and exacerbation of the bone resorption process. Elevated level of peripheral kynurenine pathway metabolites in the course of CKD may also induce changes in the activity of other signalling factors, such as the receptor activator of nuclear factor-κB ligand/osteoprotegerin axis, extracellular signal-regulated kinases, and histone deacetylase-3 or runt-related transcription factor 2 expression levels, which also may stimulate osteoclasts and inhibit osteoblast activity. Abbreviations: 3-HKYN, 3-hydroxykynurenine; AhR, Aryl hydrocarbon receptor; CYP1A1, AhR-dependent cytochrome P450, family 1, subfamily A, polypeptide 1; ERK, Extracellular signal-regulated kinases; Hdac3, Histone deacetylase-3; INF- γ, Interferon-gamma; KYN, Kynurenine; LP, Lipopolysaccharide; miRNA, micro RNA; RANKL/OPG, Receptor activator of NF-kB ligand/osteoprotegerin axis; ROS, Reactive oxygen species; Runx2, Runt-related transcription factor 2.