Spatiotemporal interaction of immune and renal cells controls glomerular crescent formation in autoimmune kidney disease
Zeba Sultana, Robin Khatri, Behnam Yousefi, Nikhat Shaikh, Saskia-Larissa Jauch-Speer, Darius P. Schaub, Jonas Engeßer, Malte Hellmig, Vincent Piegsa, Arthur L. Hube, Varshi Sivayoganathan, Alina Borchers, Anett Peters, Anna Kaffke, Stephanie Zielinski, Hans‐Joachim Paust, Thiago Goldbeck-Strieder, Ulrich Wenzel, Victor G. Puelles, Elion Hoxha, Thorsten Wiech, Catherine Meyer‐Schwesinger, Tobias B. Huber, Ulf Panzer, Stefan Bonn, Christian F. Krebs
Abstract
Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney diseases and is characterized by glomerular crescent formation with proliferation of parietal epithelial cells (PECs). However, the underlying mechanisms of glomerular crescent formation are incompletely understood. Here we provide a high-resolution spatial kidney cell atlas of 57 samples from patients with RPGN (ANCA-associated GN, lupus nephritis and anti-glomerular basement membrane-GN) to characterize the cell signaling pathways in glomerular crescent development. Early platelet-derived growth factor (PDGF) signaling from epithelial and mesangial cells caused PEC activation and proliferation in glomerular crescents, whereas later transforming growth factor (TGF)-β signaling from macrophages, T cells and epithelial and mesangial cells triggered expression of extracellular matrix components in PECs associated with glomerulosclerosis and disease progression. These findings were similar across the different GNs and were functionally validated in experimental GN by PDGF and TGFβ blockade. These results highlight a spatiotemporally conserved progression program into glomerular crescents and sclerosis and indicate new treatment options for autoimmune kidney disease.