title: Podocyte Regeneration Driven by Renal Progenitors Determines Glomerular Disease Remission and Can Be Pharmacologically Enhanced.
abstract: Podocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes. When the same model was established in inducible transgenic mice where renal progenitors are tagged, the disease remitted if renal progenitors successfully differentiated into podocytes, while it persisted if differentiation was ineffective, resulting in glomerulosclerosis. Treatment with BIO, a GSK3s inhibitor, significantly increased disease remission by enhancing renal progenitor sensitivity to the differentiation effect of endogenous retinoic acid. These results establish renal progenitors as critical determinants of glomerular disease outcome and a pharmacological enhancement of their differentiation as a possible therapeutic strategy.
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Electronic address: laura.lasagni@unifi.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Lasagni
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Angelotti
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; Department of Clinical and Experimental Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ronconi
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Duccio
authors.initials: D
authors.lastname: Lombardi
authors.affiliation: Nephrology Unit, Meyer Children's University Hospital, Viale Pieraccini 24, 50141 Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Nardi
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; Department of Clinical and Experimental Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Peired
authors.affiliation: Nephrology Unit, Meyer Children's University Hospital, Viale Pieraccini 24, 50141 Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Becherucci
authors.affiliation: Nephrology Unit, Meyer Children's University Hospital, Viale Pieraccini 24, 50141 Florence, Italy.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mazzinghi
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sisti
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Romoli
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Alexa
authors.initials: A
authors.lastname: Burger
authors.affiliation: Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesenstrasse 75, 8032 Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Schaefer
authors.affiliation: Pathology Unit, Meyer Children's Hospital, Viale Pieraccini 24, 50141 Florence, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Buccoliero
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Lazzeri
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Viale Pieraccini 6, 50139 Florence, Italy; Department of Clinical and Experimental Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; Nephrology Unit, Meyer Children's University Hospital, Viale Pieraccini 24, 50141 Florence, Italy. Electronic address: paola.romagnani@unifi.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012038:Regeneration; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000473:pathology*; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; D038362:Glycogen Synthase Kinase 3