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

Abstract

(1) The beneficial effects of hydrogen sulfide (H2S) on the cardiovascular and nervous system have recently been re-evaluated. It has been shown that lanthionine, a side product of H2S biosynthesis, previously used as a marker for H2S production, is dramatically increased in circulation in uremia, while H2S release is impaired. Thus, lanthionine could be classified as a novel uremic toxin. Our research was aimed at defining the mechanism(s) for lanthionine toxicity. (2) The effect of lanthionine on H2S release was tested by a novel lead acetate strip test (LAST) in EA.hy926 cell cultures. Effects of glutathione, as a redox agent, were assayed. Levels of sulfane sulfur were evaluated using the SSP4 probe and flow cytometry. Protein content and glutathionylation were analyzed by Western Blotting and immunoprecipitation, respectively. Gene expression and miRNA levels were assessed by qPCR. (3) We demonstrated that, in endothelial cells, lanthionine hampers H2S release; reduces protein content and glutathionylation of transsulfuration enzyme cystathionine-β-synthase; modifies the expression of miR-200c and miR-423; lowers expression of vascular endothelial growth factor VEGF; increases Ca2+ levels. (4) Lanthionine-induced alterations in cell cultures, which involve both sulfur amino acid metabolism and calcium homeostasis, are consistent with uremic dysfunctional characteristics and further support the uremic toxin role of this amino acid.

Serum Metabolome Changes in Relation to Prothrombotic State Induced by Combined Oral Contraceptives with Drospirenone and Ethinylestradiol

“…Lanthionine, a naturally occurring amino acid, which is nonproteogenic, is the byproduct of H 2 S biosynthesis from cysteine (Chiku et al, 2009;Perna et al, 2017). Lanthionine has been shown to induce an increased calcium influx in cells while inhibiting the release of H 2 S, suggesting that lanthionine may be responsible for interfering with calcium signaling while decreasing the H 2 S concentration (Vigorito et al, 2019). Increased cytosolic calcium has been shown to disrupt erythrocyte membrane integrity leading to eryptosis (Harisa et al, 2017;Mohanty et al, 2014), as previously observed in DRSP/EE users (Emmerson et al, 2018) and which will be discussed in a later section.…”

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.…”

Homocysteine and chronic kidney disease: an ongoing narrative

“…1 Metabolic interconnections of homocysteine with sulfur amino acids, folate cycle, B vitamins, and one carbon (C1) metabolism independently use cysteine to synthesize hydrogen sulfide (H 2 S; evidenced by a star), the third gaseous vasodilator, after nitric oxide and carbon monoxide, thus yielding lanthionine as a side product. Lanthionine is regarded as a novel uremic toxin [10]. Dashed circle indicates inhibition.…”