000 03377 am a22004933u 4500
042 _adc
100 1 0 _aMelica, Maria Elena
_eauthor
_92055
700 1 0 _aAntonelli, Giulia
_eauthor
_92056
700 1 0 _aSemeraro, Roberto
_eauthor
_92057
700 1 0 _aAngelotti, Maria Lucia
_eauthor
_92058
700 1 0 _aLugli, Gianmarco
_eauthor
_92059
700 1 0 _aLandini, Samuela
_eauthor
_92060
700 1 0 _aRavaglia, Fiammetta
_eauthor
_92061
700 1 0 _aLa Regina, Gilda
_eauthor
_92062
700 1 0 _aConte, Carolina
_eauthor
_92063
700 1 0 _aDe Chiara, Letizia
_eauthor
_92064
700 1 0 _aPeired, Anna Julie
_eauthor
_92065
700 1 0 _aMazzinghi, Benedetta
_eauthor
_92066
700 1 0 _aDonati, Marta
_eauthor
_92067
700 1 0 _aMolli, Alice
_eauthor
_92068
700 1 0 _aSteiger, Stefanie
_eauthor
_92069
700 1 0 _aMagi, Alberto
_eauthor
_92070
700 1 0 _aBartalucci, Niccolò
_eauthor
_92071
700 1 0 _aRaglianti, Valentina
_eauthor
_92072
700 1 0 _aGuzzi, Francesco
_eauthor
_92073
700 1 0 _aMaggi, Laura
_eauthor
_92074
700 1 0 _aAnnunziato, Francesco
_eauthor
_92075
700 1 0 _aBurger, Alexa
_eauthor
_92076
700 1 0 _aLazzeri, Elena
_eauthor
_92077
700 1 0 _aAnders, Hans-Joachim
_eauthor
_92078
700 1 0 _aLasagni, Laura
_eauthor
_92079
700 1 0 _aRomagnani, Paola
_eauthor
_92080
245 0 0 _aCrescents derive from single podocyte progenitors and a drug enhancing their differentiation attenuates crescentic glomerulonephritis*
260 _c2022-08-10.
500 _a/pmc/articles/PMC7614034/
500 _a/pubmed/35947676
520 _aCrescentic 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.
540 _a
546 _aen
690 _aArticle
655 7 _aText
_2local
786 0 _nSci Transl Med
856 4 1 _uhttp://dx.doi.org/10.1126/scitranslmed.abg3277
_zConnect to this object online.
999 _c870
_d870