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Research Article
KIDNEY DISEASE

Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice

Science Translational Medicine
10 Aug 2022
Vol 14, Issue 657

A drug that turns crescents into podocytes

Severe immune-mediated disorders often lead to kidney failure resulting from formation of glomerular crescents, which are regions of parietal epithelial hyperplasia around the glomeruli. Melica et al. show that crescents derive from clonal expansion of a subset of parietal epithelial cells that represent renal progenitor cells. Panobinostat reduced crescent formation and improved proteinuria and kidney function in a mouse model of crescentic glomerulonephritis by enhancing renal progenitor cell differentiation into podocytes. Expansion of a renal progenitor cell subset in human crescents correlated with end-stage kidney disease. These results support the concept that crescentic glomerulonephritis represents a clonal disease that can be treated with panobinostat.

Abstract

Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.

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Supplementary Materials

This PDF file includes:

Materials and Methods
Figs. S1 to S13
Tables S1 to S3
References (6879)

Other Supplementary Material for this manuscript includes the following:

Data file S1
Movie S1
MDAR Reproducibility Checklist

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Science Translational Medicine
Volume 14 | Issue 657
August 2022

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Received: 28 December 2020
Accepted: 21 March 2022

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Acknowledgments

This study was funded by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 101019891). This research was also funded by Tuscany Region Bando Ricerca Salute 2018, progetto NIKE. M.E.M. was supported by a FIRC-AIRC fellowship for Italy. A.J.P. was the recipient of the Fondazione Umberto Veronesi fellowship. H.-J.A. was supported by the Deutsche Forschungsgemeinschaft (AN372/14-4, 27-1, 30-1).
Author contributions: P.R. designed the study and analyzed the data with contributions from L.L. and M.E.M. M.E.M. performed or supervised experiments. R.S. analyzed the data from the scRNAseq analysis. M.L.A., G.A., C.C., and V.R. designed and performed immunofluorescence and confocal microscopy. B.M. carried out all scRNAseq and assisted with data analysis. S.L. validated and sequenced the single-cell libraries. L.D.C., M.D., and S.S. performed flow cytometry analysis. A.B. provided the Pax2.rtTA mouse. A.J.P., G.L.R., and A.Molli carried out mouse experiments. L.M. performed cell sorting experiments. G.L., F.R., and F.G. organized patient tissue collection, assisted with statistical analysis, and scored the human samples blinded. G.L.R. and A.Molli performed mouse genotyping and assisted with mouse experiments. G.L.R. and N.B. helped with in vitro experiments. A.Magi helped with scRNAseq analysis. F.A. assisted and advised on flow cytometry data interpretation. E.L. and H.-J.A. critically revised and edited the manuscript and advised on data interpretation. P.R. wrote the manuscript with the contribution of L.L. and M.E.M. All authors read and approved the final manuscript.
Competing interests: H.-J.A. reports paid consulting for AstraZeneca, Bayer, GSK, Novartis, Kezar, and Vifor. All other authors declare no competing interests.
Data and materials availability: All data associated with this study are present in the paper or the Supplementary Materials. scRNAseq data are available in the National Center for Biotechnology Information’s Gene Expression Omnibus repository with accession numbers GSE195784, GSE195785, and GSE195797.

Authors

Affiliations

Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Investigation and Validation.
Roberto Semeraro
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Roles: Data curation, Formal analysis, Methodology, Software, and Writing - review & editing.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Investigation, Resources, and Validation.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Project administration, and Resources.
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Investigation and Writing - review & editing.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Conceptualization, Methodology, Resources, and Validation.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Investigation, Methodology, Resources, and Validation.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Investigation and Validation.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Investigation and Validation.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Role: Investigation.
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Investigation and Methodology.
Marta Donati
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Investigation and Validation.
Alice Molli
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Investigation and Validation.
Division of Nephrology, Medizinische Klinik and Poliklinik IV, Klinikum der LMU München, Munich 80336, Germany.
Role: Investigation.
Department of Information Engineering, University of Florence, Florence, Italy.
Roles: Formal analysis and Software.
Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation of Myeloproliferative Neoplasms, AOUC, University of Florence, Florence 50139, Italy.
Role: Resources.
Valentina Raglianti
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Role: Investigation.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Formal analysis, Investigation, Resources, and Writing - review & editing.
Laura Maggi
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Roles: Methodology and Project administration.
Francesco Annunziato
Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Roles: Conceptualization, Data curation, Formal analysis, Investigation, Resources, Supervision, Validation, Visualization, and Writing - review & editing.
Section of Developmental Biology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Role: Resources.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Role: Writing - review & editing.
Division of Nephrology, Medizinische Klinik and Poliklinik IV, Klinikum der LMU München, Munich 80336, Germany.
Roles: Conceptualization, Methodology, Resources, Supervision, Validation, and Writing - review & editing.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Roles: Conceptualization, Formal analysis, Project administration, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.
Excellence Center for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence 50139, Italy.
Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence 50139, Italy.
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence 50139, Italy.
Roles: Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, and Writing - review & editing.

Funding Information

Tuscany Region

Notes

*
Corresponding author. Email: [email protected] (P.R.): [email protected] (L.L.)
These authors contributed equally to this work.

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