Glomerular cell atlas of multi-disease model revealed the characteristic changes of glomerular cell subtypes in diseases

Although a range of glomerular diseases profoundly affect glomerulus-associated cells, a comprehensive understanding of their molecular alterations is still lacking. Here, we performed in-depth analysis of glomerular data from mouse models of primary and secondary glomerulopathies and constructed a multi-disease cellular landscape of glomerular cells. We identified a putative subset of proliferative glomerular endothelial cells(gECs) that highly expresses genetic susceptibility genes associated with multiple glomerular diseases. Podocytes exhibited shared injury-associated cell types across different disease models. A podocyte subset highly expressing <i>Endou</i>, <i>Cd200</i>, <i>Lgmn</i>, <i>Il18</i>, <i>Dmpk</i>, and <i>Spon2</i> was predominantly derived from ob/ob mice, whereas another podocyte subset with high expression of <i>Selenbp1</i>, <i>Lpar1</i>, <i>S100a8</i>, <i>S100a9</i>, and <i>Sult1a1</i> was mainly observed in adriamycin-induced mice. Mesangial cells shared common injury-related alterations across diseases (high expression of <i>Cxcl1</i>, <i>egr1</i>, <i>hspa1b</i>, <i>socs3</i> and <i>dnajb1</i>), while ob/ob mice exhibited a distinct mesangial cell subset (high expression of <i>aldh1a2, thbs1</i> and <i>fbln5</i>). In contrast, the gECs displayed similar molecular changes across different diseases without giving rise to disease-specific subtypes. Intercellular ligand-receptor analysis underpins the recruitment of immune cells by injured mesangial cells and podocytes via specific engagement of pairs such as CXCL and MIF, respectively. Our study systematically elucidates the molecular alterations of glomerulus-associated cells across various diseases, providing a foundation and strategic insights for future targeted therapies tailored to specific glomerular disease contexts.