Glomerular filtration drug injury: In vitro evaluation of functional and morphological podocyte perturbations

Journal Article · Fri Dec 15 04:00:00 EST 2017 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2017.10.031· OSTI ID:22901324

Delézay, Olivier ^[1]; He, Zhiguo ^[2]; Hodin, Sophie ^[1]; Saleem, Moin A. ^[3]; Mismetti, Patrick ^[4]; Perek, Nathalie ^[1]; Delavenne, Xavier ^[1]

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1. INSERM, U1059, Dysfonction Vasculaire et Hémostase, Saint-Etienne (France)
2. Université de Lyon, Saint-Etienne F-42023 (France)
3. University of Bristol, Bristol Royal Hospital for Children, Bristol (United Kingdom)
4. Unité de Recherche Clinique Innovation et Pharmacologie, CHU de Saint-Etienne, F-42055 Saint Etienne (France)

Highlights: • The use of nephrotoxic drugs is often unavoidable. • Human podocyte cell line allows the study of the simplified glomerular filtration. • Filtration perturbations are correlated with morphological and phenotypic changes. • Functional and morphological tests are interesting tools for drug screening. The kidney is an organ that plays a major role in the excretion of numerous compounds such as drugs and chemicals. However, a great number of pharmacological molecules are nephrotoxic, affecting the efficiency of the treatment and increasing morbidity or mortality. Focusing on glomerular filtration, we propose in this study a simple and reproducible in vitro human model that is able to bring to light a functional podocyte injury, correlated with morphologic/phenotypic changes after drug exposure. This model was used for the evaluation of paracellular permeability of FITC-dextran molecules as well as FITC-BSA after different treatments. Puromycin aminonucleoside and adriamycin, compounds known to induce proteinuria in vivo and that serve here as positive nephrotoxic drug controls, were able to induce an important increase in fluorescent probe passage through the cell monolayer. Different molecules were then evaluated for their potential effect on podocyte filtration. Our results demonstrated that a drug effect could be time dependent, stable or scalable and relatively specific. Immunofluorescence studies indicated that these functional perturbations were due to cytoskeletal perturbations, monolayer disassembly or could be correlated with a decrease in nephrin expression and/or ZO-1 relocation. Taken together, our results demonstrated that this in vitro human model represents an interesting tool for the screening of the renal toxicity of drugs.

• OSTI ID: 22901324
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 2 Vol. 361; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DEXTRAN
DISEASE INCIDENCE
DOXORUBICIN
EXCRETION
FLUORESCENCE
IN VITRO
IN VIVO
INJURIES
KIDNEYS
MOLECULES
MORTALITY
PERMEABILITY
PUROMYCIN
SCREENING
TIME DEPENDENCE
TOXICITY