Kidney and liver kynurenine pathway enzymes in chronic renal failure.
ABSTRACT It has been suggested that kynurenine pathway may be an important pathological factor during the chronic renal failure (CRF) development. Therefore in the present study, in rats with end-stage of chronic renal failure, we measured the plasma and tissues (kidney and liver) concentrations of tryptophan, kynurenine, 3-hydroxykynurenine. We also evaluated the activity of tryptophan 2,3-dioxygenase in the liver (TDO), indoleamine 2,3-dioxygenase in kidney (IDO) and kynurenine 3-hydroxylase (HK) in the liver and in the kidney. The plasma and tissues tryptophan concentrations were decreased, whereas the concentrations of its metabolites increased when compared to control group. The increase in the TDO and 3-HK activity was observed, while IDO activity remains unchanged. In conclusion, the increase in the activity of TDO and HK along with disturbances of renal excreting function may be responsible for the elevation in the kynurenine and 3-hydroxykynurenine concentrations in experimental chronic renal failure.
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ABSTRACT: The risk of osteoporosis increases in inflammatory disorders. In cell-mediated immune activation, interferon gamma (IFN-γ) stimulates macrophage release of neopterin and increases the activity of indoleamine 2,3-dioxygenase (IDO), thereby stimulating tryptophan degradation along the kynurenine pathway. Plasma levels of neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Several kynurenine pathway metabolites (kynurenines) possess immunomodulatory properties. The aim was to investigate associations between markers of IFN-γ-mediated inflammation and kynurenines, with bone mineral density (BMD). The community-based Hordaland Health Study (HUSK) with middle-aged (46-49 years) and older (71-74 years) participants was conducted 1998-2000 (N=5312). Hip BMD in relation to neopterin, KTR and kynurenines were investigated, using linear and logistic regression analyses. In the oldest group, neopterin (p≤0.019), and KTR (p≤0.001) were inversely associated with BMD after multiple adjustment. Comparing the highest to the lowest quartiles, the odds ratios of low BMD (being in the lowest quintile of BMD) in the oldest cohort were for neopterin 2.01 among men and 2.34 among women, (p≤0.007), for KTR 1.80 for men and 2.04 for women (p≤0.022). Xanthurenic acid was positively associated with BMD in all sex and age groups while 3-hydroxyanthranilic acid was positively associated with BMD among women only (p≤0.010). In conclusion, we found an inverse association between BMD and markers of IFN-γ-mediated inflammation in the oldest. BMD was also associated with two kynurenines in both age groups. These results may support a role of cell mediated inflammation in bone metabolism.Clinical & Experimental Immunology 02/2014; · 3.28 Impact Factor
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ABSTRACT: This review discusses the mechanisms and consequences of degradation of tryptophan (Trp) in the placenta, focusing mainly on the role of indoleamine 2,3-dioxygenase-1 (IDO1), one of three enzymes catalyzing the first step of the kynurenine pathway of Trp degradation. IDO1 has been implicated in regulation of feto-maternal tolerance in the mouse. Local depletion of Trp and/or the presence of metabolites of the kynurenine pathway mediate immunoregulation and exert antimicrobial functions. In addition to the decidual glandular epithelium, IDO1 is localized in the vascular endothelium of the villous chorion and also in the endothelium of spiral arteries of the decidua. Possible consequences of IDO1-mediated catabolism of Trp in the endothelium encompass antimicrobial activity and immunosuppression, as well as relaxation of the placental vasotonus, thereby contributing to placental perfusion and growth of both placenta and fetus. It remains to be evaluated whether other enzymes mediating Trp oxidation, such as indoleamine 2,3-dioxygenase-2, Trp 2,3-dioxygenase, and Trp hydroxylase-1 are of relevance to the biology of the placenta.Frontiers in Immunology 01/2014; 5:230.
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ABSTRACT: Chronic kidney disease (CKD) is part of a number of systemic and renal diseases and may reach epidemic proportions over the next decade. Efforts have been made to improve diagnosis and management of CKD. We hypothesised that combining metabolomic and proteomic approaches could generate a more systemic and complete view of the disease mechanisms. To test this approach, we examined samples from a cohort of 49 patients representing different stages of CKD. Urine samples were analysed for proteomic changes using capillary electrophoresis-mass spectrometry and urine and plasma samples for metabolomic changes using different mass spectrometry-based techniques. The training set included 20 CKD patients selected according to their estimated glomerular filtration rate (eGFR) at mild (59.9±16.5 mL/min/1.73 m2; n = 10) or advanced (8.9±4.5 mL/min/1.73 m2; n = 10) CKD and the remaining 29 patients left for the test set. We identified a panel of 76 statistically significant metabolites and peptides that correlated with CKD in the training set. We combined these biomarkers in different classifiers and then performed correlation analyses with eGFR at baseline and follow-up after 2.8±0.8 years in the test set. A solely plasma metabolite biomarker-based classifier significantly correlated with the loss of kidney function in the test set at baseline and follow-up (ρ = -0.8031; p<0.0001 and ρ = -0.6009; p = 0.0019, respectively). Similarly, a urinary metabolite biomarker-based classifier did reveal significant association to kidney function (ρ = -0.6557; p = 0.0001 and ρ = -0.6574; p = 0.0005). A classifier utilising 46 identified urinary peptide biomarkers performed statistically equivalent to the urinary and plasma metabolite classifier (ρ = -0.7752; p<0.0001 and ρ = -0.8400; p<0.0001). The combination of both urinary proteomic and urinary and plasma metabolic biomarkers did not improve the correlation with eGFR. In conclusion, we found excellent association of plasma and urinary metabolites and urinary peptides with kidney function, and disease progression, but no added value in combining the different biomarkers data.PLoS ONE 01/2014; 9(5):e96955. · 3.53 Impact Factor