Table 1.

In vitro studies of the effects of UTs on cardiovascular complications.

First Author, Year	Models	UT(s) Studied	Main Findings
Arinze [50], 2022	Primary human dermal	IS	IS, kynurenine, and KA decreased Wnt/$\beta$-catenin
	microvascular ECs	Kynurenine	activity, which causes EC dysfunction and impairs
		KA	angiogenesis.
Lano [93], 2020	HUVECs	IS	IS had a prothrombotic effect by increasing TF expression in ECs and peripheral blood mononuclear cells via AHR activation.
He [80], 2019	HASMCs	IS	IS induced calcification of HASMCs via the NF-$\kappa$B signaling pathway.
Chen [81], 2016	HASMCs	IS	IS decreased Klotho expression, promoting aortic calcification.
Tang [90], 2015	Embryonic rat heart-derived cardiac H9c2 cells	IS	IS has a role in arrhythmogenesis: IS inhibited the inward rectifier potassium ion channels function, resulting in a prolonged QT interval.
Chitalia [94], 2013	HVSMCs	IS	IS increased TF expression and decreased TF ubiquitination, leading to a thrombogenic milieu.
Liu [92], 2012	Neonatal cardiac myocytes and fibroblasts from Sprague–Dawley rats	IS	IS was taken up by cardiomyocytes through OAT-1 and -3, leading to activation of the NF-$\kappa$B and MAPK pathways that are involved in cardiac hypertrophy and fibrosis.
Lekawanvijit [91], 2010	Isolated NCMs, NCFs and THP-1	IS	IS has a role in harmful cardiac remodeling: it has pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects via the activation of MAPK and NF-$\kappa$B pathways.
Tumur [62], 2010 and Ito [63], 2010	HUVECs	IS	IS increased the expression of the adhesion molecules ICAM-1, VCAM-1, MCP-1, and e-selectin, all of which are involved in the pathophysiology of atherosclerosis.
Muteliefu [51], 2009	HASMCs	IS	IS induced ROS generation and the expression of Nox4, Cbfa1, ALP, and osteopontin in VSMCs.
Yamamoto [64], 2006	VSMCs were isolated from the aortas of male Sprague–Dawley rats	IS	IS caused VSMC proliferation via activation of the p42/44 MAPK pathway, a mechanism involved in the progression of atherosclerotic lesions.
Dou [52], 2015	Cultured human endothelial cells	IAA	IAA activated the inflammatory AHR/p38MAPK/NF-$\kappa$B pathway and increased the production of endothelial ROS.
Gao [96], 2015	RBC from peripheral vein	IAA	IS and IAA caused RBC damage, which is involved
	blood of eight healthy volunteers	IS	in thrombus formation.
Gondouin [95], 2013	HUVECs	IAA	IAA increased TF expression resulting in a prothrombotic effect.
Gross [65], 2015	HUVECs and HVSMCs	PCS	PCS directly stimulated the Rho-associated protein kinase, which is involved in vascular dysfunction and vascular remodeling.
Watanabe [53], 2015	HUVECs	PCS	PCS enhanced ROS production and NADPH oxidase expression.
Meijers [66], 2009	HUVECs	PCS	PCS induced shedding of endothelial microparticles, causing endothelial dysfunction.
Schepers [58], 2007	Blood from healthy donors incubated in the presence of PCS	PCS	The presence of PCS activated pro-inflammatory leukocyte free radical production.
Dou [67], 2004	HUVECs	PCS	Both PCS and IS inhibited endothelial proliferation
		IS	and wound repair.
Huang [60], 2018	Human aortic endothelial cells	HA	HA contributed to mitochondrial fission by activating mitochondrial ROS production and Drp1 protein expression.
Shang [61], 2017	HUVECs	HA	HA, IS, and IAA increased miR-92a levels, which im-
		IS	pairs EC function.
		IAA
Nagy [97], 2017	Human islets of Langerhans from healthy donors	CMPF	CMPF inhibited insulin secretion.
Itoh [59], 2012	HUVECs	CMPF	IS induced ROS production more intensely than
		IS	CMPF did.
Bouabdallah [82], 2019	HUVECs and HASMCs	Phosphate	Phosphate and IS induced the secretion of interleuk-
		IS	in-8 from ECs, which is involved in VSMC calcification.
Jover [83], 2018	VSMCs	Phosphate	High phosphate promoted extracellular matrix calcification and upregulated osteoblast markers.
Zhang [84], 2017	HASMCs	Phosphate	High phosphate induced vascular calcification via the activation of TLR4/NF-$\kappa$B signaling.
Alesutan [85], 2017	HASMCs	Phosphate	Hyperphosphatemia upregulated aldosterone synthase expression, inducing VSMCs osteogenic transdifferentiation and calcification.
Rahabi-Layachi [68], 2015	HASMCs	Phosphate	Phosphate induced apoptosis and cell cycle arrest by blocking G1/S progression, thus reducing HASMCs proliferation.
M’Baya-Moutoula [86], 2015	Peripheral blood mononuclear cells	Phosphate	Phosphate caused vascular calcification by modulating miR-223 and decreasing osteoclastogenesis.
Ciceri [87], 2015	VSMCs	Phosphate	Phosphate caused VSMC osteoblastic differentiation and led to cell calcification.
Di Marco [69], 2013	Human coronary artery ECs	Phosphate	Hyperphosphatemia decreased annexin II expression and stiffened ECs.
Six [70], 2012	HUVECs	Phosphate	Phosphate exhibited a direct vasoconstrictor effect on aortic rings, increased phenylephrine-induced contraction, and lowered acetylcholine-induced relaxation—leading to endothelial dysfunction.
Guerrero [88], 2012	Rat aortic rings and HVSMCs	Phosphate	Phosphate reduced expression of perlecan and induced BMP-2, which is involved in the osteogenic transdifferentiation pathways and would promote cells calcification.
Shroff [89], 2010	VSMCs	Phosphate	Phosphate increased alkaline phosphatase activity and mediated calcification.
Di Marco [54], 2008	HUVECs	Phosphate	Hyperphosphatemia caused EC apoptosis by increasing ROS generation and disrupting the mitochondrial membrane potential.
Shigematsu [71], 2003	HVSMCs	Phosphate	Phosphate overload accelerated calcium deposition on arteriole walls. Moreover, phosphate led to vasoconstriction, decreased vasorelaxation, decreased NO production, stimulated ROS production, and induced ECs apoptosis.
Lee [72], 2021	HUVECs	Urea	Urea led to excessive neutrophil extracellular trap formation and thus EC dysfunction.
Maciel [73], 2018	An immortalized human EC line	Urea	Urea altered cell-to-cell junctions, leading to greater endothelial damage.
D’Apolito [55], 2018	Human arterial ECs	Urea	Abnormal high urea levels had long-lasting effects on arterial cells: urea increased mitochondrial ROS production in arterial ECs even after dialysis, which typically promotes endothelial dysfunction.
D’Apolito [56], 2017	Human endothelial progenitor cell	Urea	Urea caused ROS production and accelerated endothelial progenitor cell senescence.
Sun [75], 2016	Human arterial EC	Urea	Urea levels were positively correlated with HDL carbamylation, which inhibited endothelial repair functions.
D’Apolito [57], 2015	Human aortic ECs	Urea	Urea increased mitochondrial ROS production and inhibited GAPDH, which leads to the activation of the endothelial pro-inflammatory pathway. Furthermore, urea inactivated the anti-atherosclerosis enzyme PGI2 synthase.
Trécherel [74], 2012	HASMCs	Urea	Urea induced BAD protein expression, sensitizing the HASMCs to apoptosis.
D’Apolito [98], 2010	3T3-L1 adipocytes treated with urea	Urea	Urea increased ROS levels and expression of the adipokines retinol binding protein 4 and resistin.
Zhang [76], 2020	Aortic VSMCs from male “Sprague Dawley” rats and human VSMCs	TMAO	TMAO promoted vascular calcification through activation of the NLRP3 inflammasome and NF-$\kappa$B signals.
Ma [77], 2017	HUVECs	TMAO	HUVECs showed impairment in cellular proliferation, and TMAO induced NF-$\kappa$B signaling pathway, increasing vascular inflammatory signals and EC dysfunction.
Boini [78], 2017	Mouse carotid artery ECs	TMAO	TMAO activated NLRP3 inflammasomes, causing endothelial dysfunction.
Sun [79], 2016	HUVECs	TMAO	TMAO activated NLRP3 inflammasomes, causing endothelial dysfunction.

Abbreviations: AHR: aryl hydrocarbon receptor; ALP: alkaline phosphatase; Cbfa1: core binding factor 1; CMPF: 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; CVD: cardiovascular disease; Drp: dynamin-related protein; ECs: endothelial cells; eNOS: endothelial nitric oxide synthase; ENPP1: ectonucleotide pyrophosphate/phosphodiesterase 1; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; HA: hippuric acid; HASMC: human aortic smooth muscle cell; HDL: high-density lipoprotein; HUVECs: human umbilical vein endothelial cells; HVSMC: human vascular smooth muscle cell; IAA: indole-3-acetic acid; ICAM-1: intercellular adhesion molecule-1; IS:indoxyl sulfate; KA: kynurenic acid; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemotactic protein-1; NADPH: nicotinamide adenine dinucleotide phosphate; NCM: neonatal rat cardiac myocyte; NCF: neonatal rat cardiac fibroblast; NF-kB: nuclear factor-kappa B; NLRP3: nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3; NO: nitric oxide; PCS: para-cresyl sulfate; RBC: red blood cell; ROS: reactive oxygen species; TF: tissue factor; THP-1: human leukemia monocytic cell line; TLR4: tolllike receptor 4; TMAO: trimethylamine-N-oxide; UT: uremic toxin; VCAM-1: vascular cell adhesion molecule-1; VSMC: vascular smooth muscle cells.