Uremic Toxin–Targeting as a Therapeutic Strategy for Preventing Cardiorenal Syndrome

Abstract

Chronic kidney disease (CKD) is a global health problem. CKD patients are at high risk of developing cardiovascular disease (CVD), including coronary artery disease, heart failure and stroke. Several factors invoke a vicious cycle of CKD and CVD, which is referred as to "cardiorenal syndrome". Among these factors, the compounds retained through loss of renal excretion play a pathological role in causing atherosclerosis and CVD. These compounds have been broadly classified as uremic toxins because of their accumulation with declining renal function and cytotoxicity. The major uremic toxins contributing to CVD are asymmetric dimethylarginine (ADMA), advanced glycation endproducts (AGE), and trimethyl amine N-oxide (TMAO). ADMA is linked to CVD through regulation of nitric oxide, reactive oxygen species, and renal anemia. AGE not only directly accumulates in the heart and kidney, but interacts with the receptor for AGE (RAGE), leading to cell damage in CVD. TMAO correlates with a high prevalence of CVD and promotes organ fibrosis by itself. The levels of these and other uremic toxins rise with worsening CKD, inducing multiplicative damage in the heart and kidney. Therefore, a better understanding of uremic toxins has great clinical importance for preventing cardiorenal syndrome. This review highlights the molecular mechanism by which these uremic toxins are implicated in CVD and suggests the possible mutual relationship between them.

Cardiac Remodeling in Chronic Kidney Disease

“…The role of uremic toxins in the development of cardiac remodeling is less well established. Recent work sheds light on the potential roles of asymmetric dimethylarginine (ADMA), advanced glycation end-products (AGE), trimethylamine N-oxide (TMAO) and indoxyl sulfate [69]. ADMA has been reported to be involved in regulation of nitric oxide, reactive oxygen species and renal anemia [69,70].…”

“…Recent work sheds light on the potential roles of asymmetric dimethylarginine (ADMA), advanced glycation end-products (AGE), trimethylamine N-oxide (TMAO) and indoxyl sulfate [69]. ADMA has been reported to be involved in regulation of nitric oxide, reactive oxygen species and renal anemia [69,70]. The AGE/RAGE axis is responsible for cell damage in CVD [69], driving cardiac fibrosis.…”

“…ADMA has been reported to be involved in regulation of nitric oxide, reactive oxygen species and renal anemia [69,70]. The AGE/RAGE axis is responsible for cell damage in CVD [69], driving cardiac fibrosis. TMAO, a metabolite derived from choline, is linked with left-ventricular diastolic dysfunction [71] and cardiac fibrosis [69].…”

“…The AGE/RAGE axis is responsible for cell damage in CVD [69], driving cardiac fibrosis. TMAO, a metabolite derived from choline, is linked with left-ventricular diastolic dysfunction [71] and cardiac fibrosis [69].…”

How do Uremic Toxins Affect the Endothelium?

“…Atherosclerosis, autoimmune disease, diabetes mellitus, and inflammatory diseases are closely linked to the AGE receptor-ligand axis [ 121 , 122 , 123 , 124 ]. AGEs induce cell injury by interacting with their receptor, denominated receptor for advanced glycation end products (RAGE), which is a ubiquitous multiligand transmembrane cell surface receptor of the immunoglobulin superfamily [ 116 , 125 , 126 , 127 ]. We also previously demonstrated that AGEs induced RAGE expression in endothelial cells [ 128 ].…”