TY  - BOOK
AU  - Melica,Maria Elena
AU  - Antonelli,Giulia
AU  - Semeraro,Roberto
AU  - Angelotti,Maria Lucia
AU  - Lugli,Gianmarco
AU  - Landini,Samuela
AU  - Ravaglia,Fiammetta
AU  - La Regina,Gilda
AU  - Conte,Carolina
AU  - De Chiara,Letizia
AU  - Peired,Anna Julie
AU  - Mazzinghi,Benedetta
AU  - Donati,Marta
AU  - Molli,Alice
AU  - Steiger,Stefanie
AU  - Magi,Alberto
AU  - Bartalucci,Niccolò
AU  - Raglianti,Valentina
AU  - Guzzi,Francesco
AU  - Maggi,Laura
AU  - Annunziato,Francesco
AU  - Burger,Alexa
AU  - Lazzeri,Elena
AU  - Anders,Hans-Joachim
AU  - Lasagni,Laura
AU  - Romagnani,Paola
TI  - Crescents derive from single podocyte progenitors and a drug enhancing their differentiation attenuates crescentic glomerulonephritis*
PY  - 2022///-08-10
KW  - Text
KW  - local
N1  - /pmc/articles/PMC7614034; /pubmed/35947676
N2  - Crescentic glomerulonephritis is characterized by vascular necrosis and the formation of parietal epithelial cell (PEC) hyperplasia, but little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in several Pax2Cre reporter mouse lines revealed that crescents derive from clonal expansion of single immature PECs. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used for the treatment of hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis, and recovered kidney function. 3D confocal microscopy and STED super-resolution imaging of glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat turned the uncontrolled hyperplasia of a specific immature PEC subset into a controlled differentiation into podocytes thereby restoring the injured glomerular filtration barrier. Single cell RNA sequencing of human renal progenitor cultures identified an immature stratifin+ subset and expansion of a stratifin-expressing progenitor in human crescentic glomerulonephritis was associated with a poor outcome. Treatment of human PECs with panobinostat attenuated stratifin expression in podocyte progenitors, reduced their proliferation but promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of progenitors can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis
UR  - http://dx.doi.org/10.1126/scitranslmed.abg3277
ER  -