Zebrafish, a Novel Model System to Study Uremic Toxins: The Case for the Sulfur Amino Acid Lanthionine

Abstract

The non-proteinogenic amino acid lanthionine is a byproduct of hydrogen sulfide biosynthesis: the third endogenous vasodilator gas, after nitric oxide and carbon monoxide. While hydrogen sulfide is decreased in uremic patients on hemodialysis, lanthionine is increased and has been proposed as a new uremic toxin, since it is able to impair hydrogen sulfide production in hepatoma cells. To characterize lanthionine as a uremic toxin, we explored its effects during the early development of the zebrafish (Danio rerio), a widely used model to study the organ and tissue alterations induced by xenobiotics. Lanthionine was employed at concentrations reproducing those previously detected in uremia. Light-induced visual motor response was also studied by means of the DanioVision system. Treatment of zebrafish embryos with lanthionine determined acute phenotypical alterations, on heart organogenesis (disproportion in cardiac chambers), increased heart beating, and arrhythmia. Lanthionine also induced locomotor alterations in zebrafish embryos. Some of these effects could be counteracted by glutathione. Lanthionine exerted acute effects on transsulfuration enzymes and the expression of genes involved in inflammation and metabolic regulation, and modified microRNA expression in a way comparable with some alterations detected in uremia. Lanthionine meets the criteria for classification as a uremic toxin. Zebrafish can be successfully used to explore uremic toxin effects.

Uremic Toxin Lanthionine Interferes with the Transsulfuration Pathway, Angiogenetic Signaling and Increases Intracellular Calcium

“…The effect of lanthionine may contribute to an overall impairment of transsulfuration, thus help explaining the presence of a very high prevalence of hyperhomocysteinemia in uremia, which so far has otherwise gone unexplained. As far as the second aspect is concerned, previous evidence showed that such damaging effects do actually take place in zebrafish, although the molecular mechanism was still elusive [7]. Data presented here showed that the induction of a more reducing cellular microenvironment, due to the presence of GSH, tends to hamper lanthionine effects on the transsulfuration enzyme CBS.…”

“…Previous results have shown that lanthionine induces significant changes in the miRNA pattern in zebrafish larvae; these changes were partly comparable to some miRNA modifications detected in uremia [7]. In this work, we undertook a literature search and choose miR-200c and miR-423 since they are altered in kidney disease [14,15,16,17,18,19,20].…”

“…It has been demonstrated that this amino acid accumulates in circulation in uremia and may inhibit transsulfuration enzymes in cell cultures, possibly contributing to the hyperhomocysteinemia almost constantly associated with uremia [6]. The uremic toxin characteristic of lanthionine has been further assessed in a zebrafish animal model, where it was demonstrated that lanthionine determines significant alterations of larval cardiovascular development, together with behavioral modifications; these alterations are partly reversible upon glutathione treatment [7].…”

Gut-Derived Metabolites and Their Role in Immune Dysfunction in Chronic Kidney Disease

“…H 2 S is also significantly lower in plasma from CKD and hemodialysis patients compared to controls, while the metabolic related compounds cystathione, homolanthionine and lanthionine are significantly increased [58]. In this respect, lanthionine, a byproduct of the transsulfuration pathway found to be quite high in the plasma of CKD patients, is able to exert several toxic effects [59][60][61][62]. Lanthionine is also an end product of bacterial metabolism.…”

Novel Applications of Lead Acetate and Flow Cytometry Methods for Detection of Sulfur-Containing Molecules

“…H 2 S is biosynthesized through enzymatic reactions in human tissues, although 50% of this gas is generated by the microbiota, in the inner and outer mucus layers of the intestine [1]. In the last two decades, the metabolism and physiological roles of H 2 S and its derivatives, such as the amount released from Fe-S proteins and sulfane sulfur species, have been also related to various pathological situations [2,3]. Controversies have been raised on the physiological H 2 S active concentrations, which have been detected in the 10 −5 −10 −4 molar range [4,5].…”