Zebrafish Model-Based Assessment of Indoxyl Sulfate-Induced Oxidative Stress and Its Impact on Renal and Cardiac Development

Abstract

Kidney disease patients may have concurrent chronic kidney disease-associated mineral bone disorder and hypertension. Cardiovascular disease (CVD) and neuropathy occur due to kidney failure-induced accumulation of uremic toxins in the body. Indoxyl sulfate (IS), a product of indole metabolism in the liver, is produced from tryptophan by the intestinal flora and is ultimately excreted through the kidneys. Hemodialysis helps renal failure patients eliminate many nephrotoxins, except for IS, which leads to a poor prognosis. Although the impacts of IS on cardiac and renal development have been well documented using mouse and rat models, other model organisms, such as zebrafish, have rarely been studied. The zebrafish genome shares at least 70% similarity with the human genome; therefore, zebrafish are ideal model organisms for studying vertebrate development, including renal development. In this study, we aimed to investigate the impact of IS on the development of zebrafish embryos, especially cardiac and renal development. At 24 h postfertilization (hpf), zebrafish were exposed to IS at concentrations ranging from 2.5 to 10 mM. IS reduced survival and the hatching rate, caused cardiac edema, increased mortality, and shortened the body length of zebrafish embryos. In addition, IS decreased heart rates and renal function. IS affected zebrafish development via the ROS and MAPK pathways, which subsequently led to inflammation in the embryos. The results suggest that IS interferes with cardiac and renal development in zebrafish embryos, providing new evidence about the toxicity of IS to aquatic organisms and new insights for the assessment of human health risks. Accordingly, we suggest that zebrafish studies can ideally complement mouse model studies to allow the simultaneous and comprehensive investigation of the physiological impacts of uremic endotheliotoxins, such as IS, on cardiac and renal development.

Zebrafish as a Model of Cardiac Pathology and Toxicity: Spotlight on Uremic Toxins

“…Additionally, Tang PW et al investigated the impact of IS on the development of zebrafish embryos, especially on cardiac and renal development [ 220 ]. At 24 hpf, zebrafish were exposed to IS at concentrations ranging from 2.5 to 10 mM.…”

“…To evaluate the impact of IS on renal function, the embryos were soaked with 2.5 mM of IS at 24 hpf and injected with 50 ng of 10 kDa dextran conjugated with Rhodamine fluorescent dye into the cardiac venous sinus at 48 hpf, showing abnormal renal development after the exposure to 1.25 mM and 2.5 mM of IS. To investigate the molecular pathway involved in this alteration, the authors demonstrated that IS affected zebrafish development via the ROS and MAPK pathways, which subsequently led to inflammation in the embryos [ 220 ].…”

Preventive Action of Beta-Carotene against the Indoxyl Sulfate-Induced Renal Dysfunction in Male Adult Zebrafish via Regulations of Mitochondrial Inflammatory and β-Carotene Oxygenase-2 Actions

“…Extreme levels of IS cause endothelial dysfunction and renal injury [14,15]. The metabolomics analysis of the IS effect revealed that it causes CKD in zebrafish via elevation of IS in plasma [16] and in mice [17]. The natural accumulation of IS is known as an indicator of the progression of CKD [8].…”

“…The renal dialysis process has also failed to manage the IS-associated CKD improvement due to the binding nature of IS to albumin [20]. Furthermore, numerous studies on IS-associated CKD were investigated with an evaluation of metabolomics and genomic analysis [16,21]. Furthermore, multiple newer molecular pathways and pathological concepts remain to be explored.…”

Morphological and Functional Alterations Induced by Two Ecologically Relevant Concentrations of Lead on Danio rerio Gills

“…For decades, zebrafish has been employed as a non-mammalian model in revealing toxic mechanisms of chemicals and predicting environmental hazards [ 32 , 33 ]. Small body size, short reproductive cycle, high fecundity, and easy husbandry are among the reasons zebrafish became a popular laboratory animal for ecotoxicological studies [ 34 , 35 , 36 ].…”