Genetic Renal Diseases: The Emerging Role of Zebrafish Models

Abstract

The structural and functional similarity of the larval zebrafish pronephros to the human nephron, together with the recent development of easier and more precise techniques to manipulate the zebrafish genome have motivated many researchers to model human renal diseases in the zebrafish. Over the last few years, great advances have been made, not only in the modeling techniques of genetic diseases in the zebrafish, but also in how to validate and exploit these models, crossing the bridge towards more informative explanations of disease pathophysiology and better designed therapeutic interventions in a cost-effective in vivo system. Here, we review the significant progress in these areas giving special attention to the renal phenotype evaluation techniques. We further discuss the future applications of such models, particularly their role in revealing new genetic diseases of the kidney and their potential use in personalized medicine.

Cysteamine-bicalutamide combination treatment restores alpha-ketoglutarate and corrects proximal tubule phenotype in cystinosis

“…To extend our knowledge on the beneficial effect of the combination treatment and bring the therapy one step closer to clinical application, we evaluated the safety and efficacy in patient- phenotype, allowing to develop a personalized medicine 28 . The ctns −/− zebrafish, on the other hand, is a robust and versatile model of cystinosis with early phenotypic characteristics of the disease that can be used for the in vivo screening of novel therapeutic agents 29,30 . The fact that the improved cystine lowering-efficacy of the combination treatment could be reproduced in tubuloids from two different patients and in cystinotic zebrafish, underlines the robustness of these findings and increases the likelihood that this treatment can be successfully extrapolated to cystinosis patients in general.…”

“…improves survival of cystinotic zebrafish. Finally, we assessed the combination therapy in cystinotic zebrafish, a well-characterized in vivo model of cystinosis 29,30 . Cystinotic zebrafish displayed significantly increased levels of cystine, dysmorphic features, delayed hatching, and reduced survival compared to the controls ( Fig.…”

Screening for insulin-independent pathways that modulate glucose homeostasis identifies androgen receptor antagonists

“…On the other hand, fraxidin, dapagliflozin, and pioglitazone reduced glucose levels by 5, 12, and 11% respectively (Figure 3A), thus attributing part of their glucose lowering effect to an insulin-independent mechanism. The lack of adipose tissue (Minchin and Rawls, 2017) and the primitive nature of kidney (pronephros) function at these developmental stages (Elmonem et al, 2018) may result in an incomplete recapitulation of adipose signaling and renal function on glucose homeostasis (Defronzo, 2009). This limitation could also explain the small magnitude of glucose level reduction observed with the PPARγ agonist or SGLT2 inhibitor treatments in zebrafish ins mutants.…”

Disease Modeling To Understand the Pathomechanisms of Human Genetic Kidney Disorders

“…The zebrafish pronephros forms at around 24 hours postfertilization and consists of a pair of segmented epithelial tubules with a fused glomerulus. The pronephros is fully functional at 48 hours post-fertilization (40).…”