Uremic Toxin Lanthionine Induces Endothelial Cell Mineralization In Vitro

Abstract

Vascular calcification (VC) is a pathological event caused by the unusual deposition of minerals in the vascular system, representing the leading cause of cardiovascular mortality in chronic kidney disease (CKD). In CKD, the deregulation of calcium and phosphate metabolism, along with the effect of several uremic toxins, act as key processes conveying altered mineralization. In this work, we tested the ability of lanthionine, a novel uremic toxin, to promote calcification in human endothelial cell cultures (Ea.hy926). We evaluated the effects of lanthionine, at a concentration similar to that actually detected in CKD patients, alone and under pro-calcifying culture conditions using calcium and phosphate. In pro-calcific culture conditions, lanthionine increased both the intracellular and extracellular calcium content and induced the expression of Bone Morphogenetic Protein 2 (BMP2) and RUNX Family Transcription Factor 2 (RUNX2). Lanthionine treatment, in pro-calcifying conditions, raised levels of tissue-nonspecific alkaline phosphatase (ALPL), whose expression also overlapped with Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1) gene expression, suggesting a possible role of the latter gene in the activation of ALPL. In addition, treatment with lanthionine alone or in combination with calcium and phosphate reduced Inorganic Pyrophosphate Transport Regulator (ANKH) gene expression, a protective factor toward the mineralizing process. Moreover, lanthionine in a pro-calcifying condition induced the activation of ERK1/2, which is not associated with an increase in DKK1 protein levels. Our data underscored a link between mineral disease and the alterations of sulfur amino acid metabolisms at a cell and molecular level. These results set the basis for the understanding of the link between uremic toxins and mineral-bone disorder during CKD progression.

Zebrafish as a Model of Cardiac Pathology and Toxicity: Spotlight on Uremic Toxins

“…et al explored the effects of lanthionine, a pending uremic toxin, on the cardiovascular system of zebrafish larvae [ 217 ]. Lanthionine is a non-proteinogenic amino acid generated as a side-product of the action of trans-sulfuration enzymes in hydrogen sulfide (H 2 S) biosynthesis, and it has been demonstrated as a potential uremic toxin with several untoward effects [ 211 , 212 , 213 , 218 ]. Lanthionine has been detected in two orders of magnitude concentrations higher in hemodialysis patients compared to normal subjects, where this compound is almost undetectable in circulation [ 202 , 203 ].…”

Lab on a Chip Device for Diagnostic Evaluation and Management in Chronic Renal Disease: A Change Promoting Approach in the Patients’ Follow Up

“…Several mechanisms are involved in the progression of CKD toward ESRD, which are still not entirely clear. For example, the accumulation of uremic toxins, and especially sulfur compounds such as homocysteine and lanthionine, are among the leading culprits affecting cardiovascular risk [ 68 ]. Many clinical manifestations are related to CKD.…”

“…These overall manifestations are known as «chronic kidney disease-bone mineral disease» (CKD-BMD). CKD-MBD is strictly related to an impaired production of calcitriol, the hormone derived from vitamin D [ 68 , 69 , 70 ]. CKD is also associated with gastrointestinal problems, (hiccoughs, anorexia, gastritis, gastrointestinal bleeding, alteration in intestinal barrier permeability), which are also related to dysbiosis.…”

“…CKD affects more than 10% of the general population worldwide, amounting to >800 million individuals. Dialysis cost covers at least 2% of the overall healthcare expenditure for only 0.1–0.2% of the general population, resulting in CKD being one of the most costly non-communicable diseases [ 68 , 72 , 74 ]. The altered environment that characterizes CKD induces the accumulation of modified amino acid residues in proteins, interfering with normal protein structure and activity [ 75 , 76 ].…”

Is It All about Endothelial Dysfunction? Focusing on the Alteration in Endothelial Integrity as a Key Determinant of Different Pathological Mechanisms

“…In line with the widespread belief that endothelial dysfunction is the earliest stage of atherosclerosis, Coppola et al [ 26 ] published an in vitro study in human EC cultures (Ea.hy926) to explore the role of vascular calcification as the leading cause of cardiovascular mortality in chronic kidney disease (CKD). In particular, the authors demonstrated that the uremic toxin lanthionine, generated as a side-product of the trans-sulphuration process, is able to modify endothelial homeostasis at a concentration similar to that usually documented in CKD patients, with the expression of specific markers involved in the mineralization process.…”