ABSTRACT
Background: Chronic kidney disease (CKD) is a worldwide issue due to the high prevalence and the serious complications, including death. Kidney functions are routinely evaluated by measuring creatinine levels, which are influenced by many factors (age, sex, diet, race, and body mass). Kynurenine is the first stable metabolite in the kynurenine pathway, which is activated in the course of CKD. Kynurenine levels in plasma can be correlated to kidney functions in CKD patients. We investigated the relationship between kynurenine levels and kidney functions indicators, and the influence of some variables (sex, age, and preexisting hypertension or diabetes) on its levels in CKD patients. Material And Methods: The study included 66 CKD patients in stages 3 to 5 seen at Tishreen University Hospital, and 22 subjects served as control. Kynurenine levels were measured by using a kynurenine ELISA kit (IDK® immundiagnostik). Results: Kynurenine levels were significantly increased with the increase in CKD stage (P < .001), and were correlated with eGFR (r = -.631, P < .001), creatinine levels (r = -.464, P < .001), and urea levels (r = .528, P < .001). Kynurenine plasma levels were not influenced by age, sex, diabetes, and hypertension in CKD patients. Conclusion: Kynurenine is a promising marker for estimating kidney functions, and its relation with kidney functions is not affected by age, sex, and presence of hypertension or diabetes in CKD patients.
ABSTRACT
Failed medical therapy is a common problem in inflammatory bowel disease. P-glycoprotein (P-gp), an efflux pump encoded by MDR1 (ABCB1) gene can actively pump drugs out of cells conferring the phenotype of multidrug resistance. Various studies evoked that cyclooxygenase (COX) system may be involved in the regulation of P-gp activity. Since COX-2 isoform is overexpressed in colic inflammatory states, we examined the inhibitory effect of COX-2-inhibitors on P-gp expression and function under COX-2 stimulated conditions mediated by trinitrobenzene sulfonic acid (TNBS) in vitro, in Caco-2 cells, and in TNBS-induced colitis in mice. COX-2 and P-gp expressions were evaluated by real-time PCR and western blot. The activity of P-gp was measured by intracellular accumulation of rhodamine123 (Rho123) in Caco-2 cells and by Rho123 efflux using the intestinal everted loop method in mice. We showed that COX-2 stimulation in Caco-2 cells by 0.1mM TNBS exposure for 24h induced P-gp protein expression and activity. This activation was reversed by simultaneous COX-2-inhibitor treatment. Moreover, this effect was reproduced in vivo, in mice, where an increased P-gp expression and activity were observed 24h post intra-rectal TNBS administration. Induced P-gp expression and activity could be blocked by the oral pre-treatment with indomethacin heptyl ester (IHE) (20mg/kg). Administration of indomethacin heptyl ester had also a protective effect in TNBS-induced colitis. Our observations suggest that the inhibition of P-gp by COX-2-inhibitors could contribute to the improvement of medical response and this finding may have relevance to medical treatment of inflammatory bowel disease patients.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Trinitrobenzenesulfonic Acid/pharmacology , Up-Regulation/drug effects , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Animals , Caco-2 Cells , Colitis/drug therapy , Colitis/genetics , Colitis/metabolism , Cyclooxygenase 2/biosynthesis , Cyclooxygenase 2/genetics , Cyclooxygenase 2 Inhibitors/therapeutic use , Dinoprostone/pharmacology , Enzyme Induction/drug effects , Humans , Indomethacin/pharmacology , Inflammation/drug therapy , Inflammation/genetics , Inflammation/metabolism , Male , MiceABSTRACT
PURPOSE: Elevated expression of the ABC transporters P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) seems to correlate with multidrug resistance of cancer cells. In this study we investigated the effect of COX inhibitors in modulating P-gp and BCRP expression and P-gp activity in Caco-2 cells. METHODS: mRNA and protein expression of MDR1 and BCRP were evaluated by real time PCR and western blot respectively. The activity of P-gp was measured by intracellular accumulation of rhodamine123 or 3H-Digoxin. RESULTS: The chronic exposure of Caco-2 to indomethacin heptyl ester (indo HE) (0.4 muM) or nimesulide (10 muM) (selective COX-2 inhibitors) and naproxen (6 muM) (non selective inhibitor COX-1/COX-2) significantly decreased the expression and activity of P-gp. In contrast, the acute treatment by nimesulide and naproxen did not modify these parameters while indo HE treatment (48-72 h) caused a protein decrease and a functional inhibition of P-gp. Unexpectedly, the short-term treatment with naproxen induced an important increase of BCRP expression, but this induction was lost after long-term treatment. No modification of BCRP expression was observed after indo HE or nimesulide treatment. CONCLUSION: Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.