Elsevier

Toxicology Letters

Volume 308, 15 June 2019, Pages 34-49
Toxicology Letters

Mini review
Molecular mechanisms of protein-bound uremic toxin-mediated cardiac, renal and vascular effects: underpinning intracellular targets for cardiorenal syndrome therapy

https://doi.org/10.1016/j.toxlet.2019.03.002Get rights and content

Highlights

  • There is an abundance of mechanistic studies involving the multi-organ effect of PBUTs.

  • We gathered evidence on molecular mechanisms in PBUT-mediated cardiac, renal and vascular effect.

  • Potential therapeutic targets to block PBUT adverse effects in the CRS setting based on mechanistic studies are also outlined.

Abstract

Cardiorenal syndrome (CRS) remains a global health burden with a lack of definitive and effective treatment. Protein-bound uremic toxin (PBUT) overload has been identified as a non-traditional risk factor for cardiac, renal and vascular dysfunction due to significant albumin-binding properties, rendering these solutes non-dialyzable upon the state of irreversible kidney dysfunction. Although limited, experimental studies have investigated possible mechanisms in PBUT-mediated cardiac, renal and vascular effects. The ultimate aim is to identify relevant and efficacious targets that may translate beneficial outcomes in disease models and eventually in the clinic. This review will expand on detailed knowledge on mechanisms involved in detrimental effects of PBUT, specifically affecting the heart, kidney and vasculature, and explore potential effective intracellular targets to abolish their effects in CRS initiation and/or progression.

Section snippets

Cardiorenal syndrome: an overview

Cardiac and renal systems work bi-directionally to maintain normal function of the human body. Due to this relationship, the failure of one organ often elicits or worsens the impairment of the other, clinically known as the cardiorenal syndrome (CRS) (Ronco et al., 2008, 2010). In addition, the vascular system is highly implicated in CRS pathophysiology due to its “conduit function” as the major blood-carrying organ. The intertwining physiology of these systems perhaps can explain the high

Overview

Recently, the systemic accumulation of protein-bound uremic toxin (PBUT) has been recognized as a non-conventional contributor to CRS. PBUT is a subclass of uremic toxin consisting of solutes with molecular weight smaller than 500 Da with high protein binding affinity. Even though the unbound free form has a relatively low (hence dialyzable) molecular weight, it is greatly elevated when they form larger complexes with serum proteins, making them non-dialyzable. Additionally, PBUT equilibrium

Adverse effects of protein-bound uremic toxins and mechanisms

The complexity of CRS as a clinical syndrome translates into convoluted findings in experimental studies. The effects of PBUT on cellular functions are usually concentration-dependent – often with varied outcomes depending on “clinically-relevant settings” employed in study designs such as the incorporation of albumin to mimic plasma albumin-binding and other endpoints. Based on the current literature, we sought to narrate the detailed mechanisms of PBUT-induced cardiac, renal and vascular

Targeting critical intracellular signaling pathways activated by protein-bound uremic toxins

The rationale for targeting intracellular pathways activated by PBUTs is to inhibit biological effects exerted by PBUTs that have gained entry into cells. Ideally, intracellular targets should also be ‘activated’ in all target organs for the likeliness of wide-reaching benefits from the blockade of the targeted pathway to ultimately attenuate PBUT-mediated effects. Here, we highlight some “common” and critical molecular processes attributed to PBUT-mediated cardiac, renal and vascular effects

Summary and recommendation

In this review, we have summarized molecular mechanisms attributed to PBUT-mediated cardiac, renal and vascular pathophysiologies that are relevant to CRS and uremia. Although the studied effects of PBUTs on the cardiac, renal and vascular systems are relatively wide, ROS imbalance and inflammation are some of the most common pathophysiologies observed in all three organs. Additionally, cellular function alteration leading to pathological hypertrophy and fibrosis, as well as impairment of

Conflict of interest

The authors have no conflict of interest to declare.

Funding

This research was supported by National Health and Medical Research Council of Australia (Program Grant 1092642 and Project Grant 1087355).

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