Adriamycin does not damage podocytes of zebrafish larvae

Maximilian Schindler,Karlhans Endlich,Nicole Endlich,Marcus Johannes Moeller,Antje Blumenthal,Sridhar Muthusami

doi:10.1371/journal.pone.0242436

Maximilian Schindler, Karlhans Endlich + Show 4 more

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https://doi.org/10.1371/journal.pone.0242436

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Journal: PLOS ONE	Publication Date: Nov 13, 2020
Citations: 4	License type: CC BY 4.0

Affiliation: Greifswald University Hospital, RWTH Aachen University

Abstract

Podocytes are highly specialized epithelial cells that are essential for an intact glomerular filtration barrier in the kidney. Several glomerular diseases like focal segmental glomerulosclerosis (FSGS) are initially due to podocyte injury and loss. Since causative treatments for FSGS are not available until today, drug screening is of great relevance. In order to test a high number of drugs, FSGS needs to be reliably induced in a suitable animal model. The zebrafish larva is an ideal model for kidney research due to the vast amount of offsprings, the rapid development of a simple kidney and a remarkable homology to the mammalian glomerulus. Zebrafish larvae possess a size-selective glomerular filtration barrier at 4 days post fertilization including podocytes with interdigitating foot processes that are connected by a slit membrane. Adriamycin is an anthracycline which is often used in mice and rats to induce a FSGS-like phenotype. In this study, we aimed to induce a similar phenotype to zebrafish larvae by adding adriamycin to the tank water in different concentrations. Surprisingly, zebrafish larvae did not develop glomerular injury and displayed an intact filtration barrier after treatment with adriamycin. This was shown by (immuno-) histology, our filtration assay, in vivo imaging by 2-photon microcopy, RT-(q)PCR as well as transmission electron microscopy. To summarize, adriamycin is unable to induce a podocyte-related damage in zebrafish larvae and therefore major effort must be made to establish FSGS in zebrafish larvae to identify effective drugs by screenings.

Highlights

Chronic kidney disease (CDK) with a global prevalence of 9.1% and an increase by 29.3% since 1990 is a major burden for both patients and public healthcare [1]
The mortality of zebrafish larvae increased after the treatment with 60 μM ADR but no evident edema formation was observed
In contrast to the zebrafish larvae treated with 60 μM ADR, low dose treated larvae survived similar to the larvae of the control group (Fig 1)

Summary

Introduction

Chronic kidney disease (CDK) with a global prevalence of 9.1% and an increase by 29.3% since 1990 is a major burden for both patients and public healthcare [1]. Within CKD, Glomerulopathies are the main causes for the development of nephrotic syndromes worldwide [2]. Focal segmental glomerulosclerosis (FSGS) is a severe glomerular pathohistological condition which often results in end stage renal disease [3]. FSGS is strongly associated with podocyte damage, hypertrophy and a loss of these post-mitotic cells [4]. Accumulation of extracellular matrix and glomerular scarring follow podocyte injury [5]. Since regenerative mechanisms of podocytes are poorly understood, the renal filtration barrier is permanently affected.

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