Investigating FSGS-like injury in zebrafish larvae by nifurpirinol: efficacy and molecular insight

Abstract

Identifying effective drugs for focal segmental glomerulosclerosis (FSGS) treatment holds significant importance. Our high-content drug screening on zebrafish larvae relies on nitroreductase/metronidazole (NTR/MTZ)-induced podocyte ablation to generate FSGS-like injury. A crucial factor for successful drug screenings is minimizing variability in injury induction. For this, we introduce nifurpirinol (NFP) as a more reliable prodrug for targeted podocyte depletion. NFP showed a 2.3-fold increase in efficiency at concentrations 1,600-fold lower compared with MTZ-mediated injury induction. Integration into the screening workflow validated its suitability for the high-content drug screening. The presence of crucial FSGS hallmarks, such as podocyte foot process effacement, proteinuria, and activation of parietal epithelial cells, was observed. After the isolation of the glomeruli from the larvae, we identified essential pathways by proteomic analysis. This study shows that NFP serves as a highly effective prodrug to induce the FSGS-like disease in zebrafish larvae and is well-suited for a high-content drug screening to identify new candidates for the treatment of FSGS.NEW & NOTEWORTHY This research investigated the use of nifurpirinol in nanomolar amounts as a prodrug to reliably induce focal segmental glomerulosclerosis (FSGS)-like damage in transgenic zebrafish larvae. Through proteomic analysis of isolated zebrafish glomeruli, we were further able to identify proteins that are significantly regulated after the manifestation of FSGS. These results are expected to expand our knowledge of the pathomechanism of FSGS. mehr

Mehr zum Titel

Titel	Investigating FSGS-like injury in zebrafish larvae by nifurpirinol: efficacy and molecular insight
Medien	American Journal of Physiology. Renal Physiology
Heft	3
Band	327
ISSN	1522-1466
Verfasser	Marianne Klawitter, Francescapaola Mattias, Felix Kliewe, Elke Hammer, Uwe Völker, Prof. Dr. Stefan Simm, Florian Siegerist, Sophie Daniel, Maximilian Schindler, Nicole Endlich
Seiten	F463–F475
Veröffentlichungsdatum	9.2024
Zitation	Klawitter, Marianne; Mattias, Francescapaola; Kliewe, Felix; Hammer, Elke; Völker, Uwe; Simm, Stefan; Siegerist, Florian; Daniel, Sophie; Schindler, Maximilian; Endlich, Nicole (2024): Investigating FSGS-like injury in zebrafish larvae by nifurpirinol: efficacy and molecular insight. American Journal of Physiology. Renal Physiology 327 (3), F463–F475. DOI: 10.1152/ajprenal.00116.2024