Nephrotoxic Effects in Zebrafish after Prolonged Exposure to Aristolochic Acid

Abstract

With the aim to explore the possibility to generate a zebrafish model of renal fibrosis, in this study the fibrogenic renal effect of aristolochic acid I (AAI) after immersion was assessed. This compound is highly nephrotoxic able to elicit renal fibrosis after exposure of rats and humans. Our results reveal that larval zebrafish at 15 days dpf (days post-fertilization) exposed for 8 days to 0.5 µM AAI showed clear signs of AKI (acute kidney injury). The damage resulted in the relative loss of the functional glomerular filtration barrier. Conversely, we did not observe any deposition of collagen, nor could we immunodetect α-SMA, a hallmark of myofibroblasts, in the tubules. In addition, no increase in gene expression of fibrogenesis biomarkers after whole animal RNA extraction was found. As zebrafish have a high capability for tissue regeneration possibly impeding fibrogenic processes, we also used a tert−/− zebrafish line exhibiting telomerase deficiency and impaired tissue homeostasis. AAI-treated tert−/− larvae displayed an increased sensitivity towards 0.5 µM AAI. Importantly, after AAI treatment a mild collagen deposition could be found in the tubules. The outcome implies that sustained AKI induced by nephrotoxic compounds combined with defective tert−/− stem cells can produce a fibrotic response.

Spatiotemporal imaging and pharmacokinetics of fluorescent compounds in zebrafish eleuthero-embryos after different routes of administration

“…Particularly, the semi-transparent appearance in combination with the ex-utero development has made it possible to screen for developmental effects after compound exposure using nothing more than a low magnification microscope. Ever since transgenic technology has become widely established and zebrafish with fluorescent highlighted organs could be generated 2 , more detailed screens for organ specific toxicities such as hepato- 6 – 8 , nephro- 9 cardio- 8 , 10 , and neurotoxicity 8 , 11 using fluorescence microscopy has emerged. In addition, it has been established that zebrafish can determine toxicity of pharmaceuticals and chemicals in general, with a specificity of 89–90%, sensitivity of 68–80%, and an accuracy of 78% 8 , 12 .…”

Spatiotemporal Imaging and Pharmacokinetic of Fluorescent Compounds in Zebrafish Eleuthero-Embryos After Different Routes of Administration

“…Ever since transgenic technology has become widely established and zebrafish with fluorescent highlighted organs could be generated [ 2 ], more detailed screens for organ specific toxicities such as hepato-[ [6][7][8] ], nephro- [ 9 ] cardio- [ 8,10 ], and neurotoxicity [ 8,11 ] using fluorescence microscopy has emerged. In addition, it has been established that zebrafish can determine toxicity of pharmaceuticals and chemicals in general, with a specificity of 89-90%, sensitivity of 68-80%, and an accuracy of 78% [ 8,12 ].…”

Neurodevelopmental toxicity of pyrazinamide to larval zebrafish and the restoration after intoxication withdrawal

“…For instance, the fish being treated until 120 hpf were continuously exposed to PZA and only used for the observation at 120 hpf. The surviving ones were anesthetized in tricaine (Xixin Wang et al, 2020) and positioned in 0.1% regular agarose G‐10 (111860, Biowest, Shanghai, China) in Milli‐Q water for examination using a stereomicroscope (Olympus SZX16, Tokyo, Japan) with cellSens Standard software 2.2. The major dysmorphologies analysis, including the hatching, malformation, and survival (yolk sac coagulation and cardiac arrest were defined as death) rate, was performed with Microsoft Excel.…”