Abstract
Acute renal failure (ARF) is a clinical critical syndrome with rapid and severe decline of renal function. Complications of ARF, especially its cardiac complications (cardiorenal syndrome type 3, CRS-3), are the main causes of death in patients with ARF. However, the shortage and limited efficacy of therapeutic drugs make it significant to establish new large-scale drug screening models. Based on the Nitroreductase/Metronidazole (NTR/MTZ) cell ablation system, we constructed a Tg(cdh17:Dendra2-NTR) transgenic zebrafish line, which can specifically ablate renal tubular epithelial cells. The absence of renal tubular epithelial cells can lead to ARF in zebrafish larvae. The ARF symptoms, such as heart enlargement, slow heart rate and blood stasis, are similar to the clinical manifestations of human CRS-3. Furthermore, two therapeutic drugs (digoxin and enalapril) commonly used in the clinical treatment of heart failure were also effective in alleviating the symptoms of CRS-3 in zebrafish, which proved the effectiveness of this model. Drug screening further discovered a potential drug candidate, α-lipoic acid, which can effectively alleviate the symptoms of CRS-3 through its antioxidant function. Accordingly, we established a new ARF model of zebrafish, which laid a foundation for large-scale screening of new therapeutic drugs for its complications.
Highlights
Our results showed that the FITC-inulin removal degree in Acute renal failure (ARF) fish was significantly reduced compared with the control group, which confirmed the loss of renal function in the zebrafish ARF model (Figure 3B,C)
We found the average beat per minute (BPM) of the control group fluctuated between 201 and 255, while the average beats per minute (BPM) of ARF larvae gradually decreased from 1 dpi to 4 dpi (177, 155, 135 and 95) (Figure 4A–C; Video S1)
In order to further verify the effectiveness of the zebrafish CRS-3 model, two FDAapproved heart failure drugs were selected to treat ARF larvae, and the efficacy was evaluated by the heart, blood vessels and survival rate
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Zebrafish can be used to establish a large-scale drug screening model for ARF complications. The NTR/MTZ system has been successfully utilized to induce conditional targeting of a variety of cell ablations for regeneration studies in zebrafish, such as renal podocytes [9,10,11], cerebrovascular cells [12], liver cells [13]. In order to obtain zebrafish ARF models with complete acute renal tubular ablation, we generated the Tg(cdh: Dendra2-NTR) transgenic zebrafish line. Upon exposure to MTZ, transgenic zebrafish larvae showed symptoms similar to human ARF, such as edema, heart enlargement, slow heart rate and blood stasis. The positive effects observed verified the applicability of drug screening with the zebrafish larvae ARF model. We constructed a new zebrafish ARF model, which lays a foundation for further screening of potential therapeutic drugs for the treatment of clinical CRS-3 or other ARF complications
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