Molecular Mechanisms Underlying the Cardiovascular Toxicity of Specific Uremic Solutes

Abstract

Mounting evidence strongly suggests a causal link between chronic kidney disease (CKD) and cardiovascular disease (CVD). Compared with non-CKD patients, patients with CKD suffer disproportionately from CVD and derive suboptimal benefits from interventions targeting conventional CVD risk factors. Uremic toxins (UTs), whose plasma levels rapidly rise as CKD progresses, represent a unique risk factor in CKD, which has protean manifestations on CVD. Among the known UTs, tryptophan metabolites and trimethylamine N-oxide are well-established cardiovascular toxins. Their molecular mechanisms of effect warrant special consideration to draw translational value. This review surveys current knowledge on the effects of specific UTs on different pathways and cell functions that influence the integrity of cardiovascular health, with implication for CVD progression. The effect of UTs on cardiovascular health is an example of a paradigm in which a cascade of molecular and metabolic events induced by pathology in one organ in turn induces dysfunction in another organ. Deciphering the molecular mechanisms underlying such cross-organ pathologies will help uncover therapeutic targets to improve the management of CVD in patients with CKD.

Keywords: cardiovascular disease; chronic kidney disease; uremic toxins.

Figure 1

Pleotropic effects of uremic toxins on various cells involved in CKD-associated cardiovascular disease.

Figure 2

Examples of molecular mechanisms underlying the effects of uremic toxins on various cells, with focus on the aryl hydrocarbon receptor signaling (AHR) pathway. Indolic uremic solutes and kynurenine, all tryptophan metabolites, are agonists of the AHR pathway. These solutes enter cells through the organic anion transport channel (OAT) in target cells. Upon binding to the cytosolic AHR protein, the ligand-bound AHR (represented as a red circle on AHR) elicits distinct signaling cascades in various cell types. In endothelial cells, AHR activation regulates cell permeability through Src and prothrombotic propensity through tissue factor (TF) activation or through p38 mitogen-activated protein kinase (MAPK) signaling. AHR activation in vSMCs induces thrombosis through TF stabilization and by activating the NF-κB pathway. In macrophages, AHR induces a proinflammatory state by increasing reactive oxygen species, and through the NF-κB-MAPK signaling cascade.