Abstract
ABSTRACTDifferent glomerular diseases that affect podocyte homeostasis can clinically present as nephrotic syndrome with massive proteinuria, hypoalbuminemia, hyperlipidemia and edema. Up to now, no drugs that specifically target the actin cytoskeleton of podocytes are on the market and model systems for library screenings to develop anti-proteinuric drugs are of high interest. We developed a standardized proteinuria model in zebrafish using puromycin aminonucleoside (PAN) via treatment in the fish water to allow for further drug testing to develop anti-proteinuric drugs for the treatment of glomerular diseases. We noticed that fish that carry the nacre-mutation show a significantly higher susceptibility for the disruption of the glomerular filtration barrier following PAN treatment, which results in a more pronounced proteinuria phenotype. Nacre zebrafish inherit a mutation yielding a truncated version of microphthalmia-associated transcription factor/melanogenesis associated transcription factor (mitf). We hypothesized that the nacre mutation may lead to reduced formin expression and defects in cytoskeletal rearrangement. Based on the observations in zebrafish, we carried out a PAN treatment on cultured human podocytes after knockdown with MITF siRNA causing a rearrangement of the actin cytoskeleton.
Highlights
Glomerular diseases that primarily affect podocyte function are often associated with the development of nephrotic syndrome which presents itself with proteinuria, hypoalbuminemia, hyperlipidemia and edema (Orth and Ritz, 1998)
Influence of genetic background on the proteinuria phenotype We wanted to test whether the genetic background of the zebrafish strains affects sensitivity towards puromycin aminonucleoside (PAN) treatment
All zebrafish larvae were treated with 4 mg/ml PAN at 46 hpf and fluorescent signal in the retinal vessels was detected at 96 hpf
Summary
Glomerular diseases that primarily affect podocyte function are often associated with the development of nephrotic syndrome which presents itself with proteinuria, hypoalbuminemia, hyperlipidemia and edema (Orth and Ritz, 1998). Focal segmental glomerulosclerosis (FSGS), membranous glomerulonephropathy (MGN), minimal change disease (MCD) and late stage diabetic nephropathy are most commonly associated with nephrotic syndrome. Therapeutic options for nephrotic syndrome are limited to supportive treatment options with RAAS-blockade, statins and treatment of other renal risk factors. In the case of FSGS, MCD and MGN immunosuppressive. Received 13 November 2018; Accepted 22 January 2019 therapy is frequently added with a high rate of potentially life threatening side effects. There is a high demand for novel and more podocyte-specific treatment concepts
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