Oxidative Storm Induced by Tryptophan Metabolites: Missing Link between Atherosclerosis and Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) occurrence is rising all over the world. Its presence is associated with an increased risk of premature death from cardiovascular disease (CVD). Several explanations of this link have been put forward. It is known that in renal failure, an array of metabolites cannot be excreted, and they accumulate in the organism. Among them, some are metabolites of tryptophan (TRP), such as indoxyl sulfate and kynurenine. Scientists have become interested in them in the context of inducing vascular damage in the course of chronic kidney impairment. Experimental evidence suggests the involvement of TRP metabolites in the progression of chronic kidney disease and atherosclerosis separately and point to oxidative stress generation as one of the main mechanisms that is responsible for worsening those states. Since it is known that blood levels of those metabolites increase significantly in renal failure and that they generate reactive oxygen species (ROS), which lead to endothelial injury, it is reasonable to suspect that products of TRP metabolism are the missing link in frequently occurring atherosclerosis in CKD patients. This review focuses on reports that shed a light on TRP metabolites as contributing factors to vascular damage in the progression of impaired kidney function.

SGLT2 inhibitors improve kidney function and morphology by regulating renal metabolic reprogramming in mice with diabetic kidney disease

“…However, a previous study found that P5P phosphatase (a cofactor for KYNase and a key enzyme regulating the 3-hydroxykynurenine metabolism downstream) is inhibited owing to chronic inflammation in DKD, which blocks tryptophan metabolism to produce NAD+ through the KYN pathway [ 53 ]. This finding is consistent with the accumulation of KYN and its metabolites (3-hydroxykynurenine [3-HKYN] and kynurenic acid [KYNA]) observed in chronic kidney disease such as DKD [ 47 ]. The accumulation of KYN and its metabolites mediate and enhance oxidative stress, immune activation and inflammatory reaction to exacerbate renal damage [ 47 ].…”

“…Tryptophan and its metabolites are precursors to various microbial biosynthetic products and metabolites of the host [ 46 ]. The following three pathways are currently associated with tryptophan catabolism: (1) serotonin (5-hydroxytryptamine) metabolism, (2) the indole pathway and (3) the kynurenine (KYN) pathway [ 47 ]. Approximately 90% of 5-HT in the body is metabolized by gut bacteria, with the most typical bacteria being Clostridium sporogenes belonging to the phylum Firmicutes [ 46 ].…”

Clinical significance of HEp-2 cell cytoplasmic patterns in anti-neutrophil cytoplasmic antibody associated vasculitis

“…The tryptophan may also cause atherosclerosis through the release of reactive oxygen species that cause endothelial damage. [ 26 ] Uremic pericarditis, pericardial effusion and chronic left heart failure were common clinical manifestations in patients with end stage renal disease. [ 27 ] It was suggested that accumulation of toxic metabolites may play an important role in cardiovascular damage in end stage renal disease patients.…”

Serum Bilirubin Levels and Extent of Symptomatic Intracranial Atherosclerotic Stenosis in Acute Ischemic Stroke: A Cross-Sectional Study

“…The mechanisms by which bilirubin functions in ICAS remains unclear, but prior studies indicate that bilirubin could inhibit atherosclerosis in several ways. First, reactive oxygen species promote lipid peroxidation, endothelial cell injury, smooth muscle cell proliferation and migration, inflammatory factor expression, and foam cell formation, leading to atherosclerosis and ultimately cerebral ischemia (37)(38)(39). Bilirubin, as the main end-product of heme metabolism, can scavenge free radicals and reduce the production of reactive oxygen species, thereby reducing the progression of atherosclerosis (40,41).…”