Table 2.

Animal studies of the effects of UTs on cardiovascular complications.

First Author, Year	Models	UT(s) Studied	Main Findings
			Atheromatous CVDs
Arinze [50], 2022	Adenine-induced	IS	IS, kynurenine, and KA suppressed Wnt/$\beta$-
	CKD mice and IS so-	Kynurenine	catenin signaling through increased AHR activity,
	lute-specific C57BL/6	KA	leading to impaired angiogenesis and hindlimb
	mice		ischemia.
Hung [101], 2016	Mice with subtotal nephrectomy	IS	IS decreased endothelial progenitor cells mobilization and impaired neovascularization, leading to PAD.
Han [103], 2016	5/6 nephrectomized ApoE –/– mice	PCS	PCS promoted the formation of atherosclerotic lesions, induced plaque instability and the migration and proliferation of VSMCs, and disturbed the balance between matrix metalloproteinases and tissue inhibitor of metalloproteinases within the plaques.
Huang [60], 2018	5/6 nephrectomized rat model	HA	HA caused pro-atherogenic effects by contributing to endothelial dysfunction via greater oxidative stress and impaired endothelium-dependent vasodilation.
Shang [61], 2017	Male Wistar rats	HA	HA induced miR-92a, which is involved in angiogenic and atherosclerotic processes.
Massy [107], 2005	ApoE −/− mice with partial kidney ablation	Urea	Urea contributed to arterial calcification and aggravated atherosclerosis.
Matsumoto [102], 2020	Superior mesenteric arteries and femoral arteries of rat	TMAO	TMAO impaired endothelium-derived hyperpolarizing factor-type relaxation, which led to PAD.
Geng [104], 2018	Apoe −/− mice fed a high-fat diet with or without TMAO	TMAO	TMAO enhanced the expression of CD36/MAPK/JNK pathway, promoting foam cells formation and, ultimately, atherosclerosis.
Seldin [105], 2016	Female low-density lipoprotein receptor knockout mice injected with vehicle or TMAO	TMAO	TMAO induced vascular inflammation by activating MAPK and NF-$\kappa$B signaling, thus enhancing atherosclerosis.
Koeth [106], 2013	Mice supplemented with dietary TMAO, carnitine, or choline	TMAO	TMAO accelerated atherosclerosis and was linked to major cardiac events.
			Non-atheromatous CVDs
Kuo [108], 2020	Nephrectomized male C57BL/6 mice	IS	IS promoted calcification in the aorta and peripheral arteries, with low NO production and high eNOS phosphorylation.
Opdebeeck [109], 2019	42 male Wistar rats ex-	IS	Both IS and PCS directly promoted severe calcifica-
	posed to adenine sulfate for 10 days and then fed a phosphate-enriched diet	PCS	tion in the aorta and peripheral vessels via activation of inflammation and coagulation pathways. These changes were strongly associated with impaired glucose homeostasis.
Chen [81], 2016	5/6 nephrectomized Sprague Dawley rats treated with IS	IS	IS decreased Klotho expression and promoted aortic calcification.
Chen [121], 2015	Isolated rabbit left atrium, right atrium, pulmonary vein, and sinoatrial nodes before and after treatment with IS	IS	IS may contribute to atrial fibrillation: It increased pulmonary vein and atrial arrhythmogenesis through oxidative stress, inflammation, and fibrosis.
Yisireyili [119], 2013 and Lekawanvijit [120], 2012	Dahl salt-sensitive hypertensive rats	IS	IS aggravated cardiac fibrosis and cardiomyocyte hypertrophy, with greater levels of oxidative stress and lower anti-oxidative defenses.
Muteliefu [110], 2012	Aorta of subtotally nephrectomized Dahl salt-sensitive hypertensive rats	IS	IS accelerated VSMC senescence and vascular calcification, with upregulation of p21, p53, and prelamin A through oxidative stress.
Adijiang [111], 2010	Dahl salt-sensitive hypertensive rats	IS	IS increased aortic calcification and wall thickness; induced expression of p16, p21, p53 and Rb in the calcification area; and thus promoted cell senescence.
Adijiang [112], 2008	Dahl salt-sensitive hypertensive rats	IS	IS induced aortic calcification (with expression of osteoblast-specific proteins) and aortic wall thickening.
Han [126], 2015	5/6 nephrectomized mice	PCS	PCS promoted cardiac apoptosis and diastolic dysfunction by upregulating the expression of NADPH oxidase and the production of ROS.
Hu [123], 2015	Two CKD rodent models: UNX-IRI26 and 5/6 nephrectomized	Phosphate	High phosphate was associated with lower Klotho levels, leading to cardiac hypertrophy and fibrosis.
Yamada [116], 2014	Adenine-induced CKD male Sprague–Dawley rats	Phosphate	High phosphate directly increased the expression of TNF-$\alpha$ and osteochondrogenic markers, inducing systemic inflammation and vascular calcification.
Lau [114], 2013	DBA/2 mice with partial renal ablation	Phosphate	High phosphate was associated with arterial medial calcification.
Crouthamel [113], 2013	Mice with targeted deletion of PiT-1 in VSMCs	Phosphate	High phosphate induced calcification of VSMCs.
El-Abbadi [115], 2009	Female DBA/2 mice induced uremia with left total nephrectomy	Phosphate	High phosphate was associated with extensive arterial medial calcification.
Graciolli [117], 2009	5/6 nephrectomized Wistar rats with parathyroidectomy	Phosphate	Phosphate upregulated aortic expression of Runx2 and led to calcified VSMC.
Hosaka [118], 2009	5/6 nephrectomized male Sprague-Dawley rats	Phosphate	High phosphate induced elastin degradation via the upregulation of tissue-nonspecific alkaline phosphatase, accelerating the transformation of VSMCs into osteoblast-like cells and leading to medial layer calcification.
Zhu [122], 2021	25 nephrectomized SPF-grade male Sprague–Dawley rats	Urea	Urea caused myocardial hypertrophy.
Prommer [124], 2018	11 uremic mice and 8 controls	Urea	Urea led to systemic microvascular disease, with microvascular rarefaction, tissue hypoxia, and dysfunctional angiogenesis.
Carmona [125], 2011	2 groups of 30 Wistar male rats: 1 with renal ablation and the other with kidney manipulation only	Urea	Urea induced systemic inflammation and led to the thickening of subepicardiac arteries.
			Other than ATH and non ATH CVDs
Yang [127], 2017	C57BL/6J mice with left total nephrectomy	IS	IS activated ROS/p38 MAPK signaling and reduced Klotho expression, which induced platelet aggregation and thrombus formation.
Kolachalama [128], 2018	A group of C57BL/6 mice administered Kyn, the excretion of which was inhibited by probenecid	Kynurenine	High kynurenine levels promoted clotting in response to vascular injury.
Koppe [133], 2017	5/6 nephrectomized	PCS	PCS (but not PCG) promoted insulin resistance.
	mice	PCG
Koppe [134], 2013	CD1 Swiss and C57BL/6J mice with 5/6 nephrectomy	PCS	PCS contributed to insulin resistance: It altered insulin signaling in skeletal muscle through the activation of extracellular signal-regulated kinases.
Nagy [97], 2017	Male CD1 mice injected with CMPF	CMPF	CMPF inhibited insulin secretion.
Koppe [130], 2016	C57BL/6N male mice with 5/6 nephrectomy	Urea	Urea increased oxidative stress and protein O-GlcNAcylation, impairing insulin secretion and glycolysis.
Carracedo [131], 2013	5/6 nephrectomized 40 male Wistar rats	Urea	Urea induced oxidative stress, leading to EC damage.
D’Apolito [98], 2010	5/6 nephrectomized C57BL/6J wild-type mice	Urea	Urea increased ROS production and induced insulin resistance and glucose intolerance.
Li [132], 2018	5/6 nephrectomized rats	TMAO	High TMAO levels decreased NO production, contributing to endothelial dysfunction.
Zhu [129], 2016	Carotid artery thrombosis models of germ-free C57BL/6J female mice	TMAO	TMAO enhanced submaximal stimulus-dependent platelet activation, increasing the thrombosis risk.

Abbreviations: CMPF: 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; CVD: cardiovascular disease; eNOS:endothelial nitric oxide synthase; HA: hippuric acid; IS:indoxyl sulfate; KA: kynurenic acid; MAPK: mitogen-activated protein kinase; MI: myocardial infarction; NADPH: nicotinamide adenine dinucleotide phosphate; NO: nitric oxide; PAD: peripheral artery disease; PCS: para-cresyl sulfate; PCG: p-cresyl glucuronide; ROS: reactive oxygen species; Runx2: runt-related transcription factor 2; TMAO: trimethylamine-N-oxide; UT: uremic toxin; VSMC: vascular smooth muscle cell.