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

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. Description Glomerular crescents derive from clonal expansion of progenitor cells, and a drug enhancing their differentiation into podocytes attenuates glomerulonephritis. 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.