Molecular insights into the early stage of glomerular injury in IgA nephropathy using single-cell RNA sequencing

Kidney Int. 2022 Apr;101(4):752-765. doi: 10.1016/j.kint.2021.12.011. Epub 2021 Dec 28.


IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and defined by the presence of IgA-containing immune complexes in the mesangium that induce an inflammation leading to glomerulonephritis. Since we poorly understand early mechanisms of glomerular injury in IgAN we performed single-cell RNA sequencing (scRNA-seq) analysis of glomerulus-associated cells using SMARTseq2-technology at the early stage of IgAN in grouped ddY-mice. Cell-specific molecular signatures unraveled a key role of endothelial cells in the early pathogenesis of IgAN, especially in the recruitment and infiltration of immune cells. Mesangial and podocyte cells demonstrated less molecular changes. Several intra-glomerular paracrine pathways were detected, such as mesangial cell-derived Slit3 potentially activating Robo-receptors in podocyte/endothelial cells. Surprisingly, proximal tubular cells were strongly affected at the early stage and potential glomerulo-tubular cell-cell crosstalk pathways were identified. Importantly, many of the cellular transcriptomic signatures identified in this well-established mouse model were also detected in published bulk transcriptomic data in human IgAN. Moreover, we validated the functionality of key cell-cell crosstalk pathways using cell culture models, such as the effect of the Slit-Robo signalling axis. Thus, our study provides important novel molecular insights into the pathogenesis of early IgAN-associated glomerulopathy.

Keywords: IgA nephropathy; glomerulus; single-cell sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endothelial Cells / pathology
  • Female
  • Glomerular Mesangium / pathology
  • Glomerulonephritis* / metabolism
  • Glomerulonephritis, IGA*
  • Humans
  • Immunoglobulin A / metabolism
  • Kidney Glomerulus / pathology
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Sequence Analysis, RNA


  • Immunoglobulin A
  • Membrane Proteins
  • Slit3 protein, mouse