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.

Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice / Maria Elena Melica, Giulia Antonelli, Roberto Semeraro, Maria Lucia Angelotti, Gianmarco Lugli, Samuela Landini, Fiammetta Ravaglia, Gilda La Regina, Carolina Conte, Letizia De Chiara, Anna Julie Peired, Benedetta Mazzinghi, Marta Donati, Alice Molli, Stefanie Steiger, Alberto Magi, Niccolò Bartalucci, Valentina Raglianti,, Francesco Guzzi, Laura Maggi, Francesco Annunziato, Alexa Burger, Elena Lazzeri, Hans-Joachim Anders, Laura Lasagni, Paola Romagnani. - In: SCIENCE TRANSLATIONAL MEDICINE. - ISSN 1946-6242. - ELETTRONICO. - (2022), pp. 0-0.

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

Maria Elena Melica;Giulia Antonelli;Roberto Semeraro;Maria Lucia Angelotti;Gianmarco Lugli;Samuela Landini;Gilda La Regina;Carolina Conte;Letizia De Chiara;Anna Julie Peired;Alberto Magi;Niccolò Bartalucci;Valentina Raglianti;Francesco Guzzi;Laura Maggi;Francesco Annunziato;Elena Lazzeri;Laura Lasagni
;
Paola Romagnani
2022

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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Maria Elena Melica, Giulia Antonelli, Roberto Semeraro, Maria Lucia Angelotti, Gianmarco Lugli, Samuela Landini, Fiammetta Ravaglia, Gilda La Regina, Carolina Conte, Letizia De Chiara, Anna Julie Peired, Benedetta Mazzinghi, Marta Donati, Alice Molli, Stefanie Steiger, Alberto Magi, Niccolò Bartalucci, Valentina Raglianti,, Francesco Guzzi, Laura Maggi, Francesco Annunziato, Alexa Burger, Elena Lazzeri, Hans-Joachim Anders, Laura Lasagni, Paola Romagnani
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1261954
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