Contribution of quinolinic acid in the development of anemia in renal insufficiency.
Quinolinic acid (QA) is a potent endogenous excitotoxin; elevation of its concentration in an organism has been implicated in the pathogenesis of various disorders. The purpose of this study was the assessment of QA impact on the process of erythropoiesis. Marked increase of QA concentration was observed in plasma and peripheral tissues of uremic rats. These changes were proportional to the amount of the removed renal tissue and positively correlated with the concentration of creatinine but negatively correlated with hematological parameters, i.e., hematocrit and Hb red blood cells count. The changes were accompanied by a slight decrease in the concentration of endogenic erythropoietin (EPO) in the plasma of animals with uremia. Chronic treatment with QA diminished the increase in EPO concentration after introduction of cobalt in rats. These changes were associated with the decrease in all hematological parameters after QA administration. The in vitro study in the conditions of hypoxia showed that QA inhibited the EPO release from HepG2 cells to the culture base. Additionally, in HepG2 cells QA had a dose-dependent inhibitory effect on hypoxia- and cobalt-induced EPO gene expression without any cell toxicity. In conclusion, the erythropoiesis in chronic renal failure could be attributed to the influence of QA on EPO synthesis. Thus we propose that QA can be a uremic toxin responsible for anemia in animals or patients with renal failure.
Pawlak
Dariusz
D
Department of Pharmacodynamics, Medical Academy, 15-230 Bialystok, Poland. daruszpawlak@poczta.onet.pl
Koda
Mariusz
M
Pawlak
Sebastian
S
Wolczynski
Slawomir
S
Buczko
Wlodzimierz
W
D000740:Anemia / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D003035:Cobalt / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects; D004921:Erythropoietin / Q000097:blood / Q000235:genetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000503:physiopathology*; D008297:Male; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D009928:Organ Specificity; D017378:Quinolinic Acid / Q000378:metabolism* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
D009498:Neurotoxins; D012333:RNA, Messenger; D004921:Erythropoietin; D003035:Cobalt; C018021:cobaltous chloride; D017378:Quinolinic Acid