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<p> Crescentic glomerulonephritis (CrGN) is a severe histological phenotype of immune mediated kidney disease. Although NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation has been implicated in CrGN, its involvement in human glomerular components remains unclear. We reanalyzed publicly available glomerular microarray data from patients with glomerular diseases. We also integrated the mixture matrix from this microarray data with the signature matrix from single nucleus RNA sequencing data using BayesPrism-based deconvolution. NLRP3 inflammasome pathway activity was assessed by gene set variation analysis and validated by immunostaining for NLRP3 using human kidney biopsy specimens. Furthermore, we conducted <i>in vivo</i> experiments using a rat CrGN model treated with shikonin known as an NLRP3 inflammasome inhibitor. NLRP3 inflammasome pathway activation was most prominent in anti-neutrophil cytoplasmic antibody-associated vasculitis. Deconvolution analysis demonstrated increased NLRP3 inflammasome pathway activity across podocytes, parietal epithelial cells (PECs), endothelial cells, and mesangial cells. Human kidney biopsy specimens confirmed increased NLRP3 expression in podocytes and PECs. In the rat CrGN model, shikonin reduced proteinuria, serum creatinine, crescent formation, and podocyte injury, accompanied by decreased expression of NLRP3 inflammasome related genes, and reduced NLRP3 protein expression in podocytes and parietal epithelial cells. NLRP3 inflammasome activation in glomerular resident cells may contribute to AAV-associated CrGN pathogenesis, and pharmacological modulation of this pathway could represent a therapeutic strategy for CrGN.</p>

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Comprehensive Transcriptomic Analysis with Deconvolution and In Vivo Experiments Reveal the Role of the NLRP3 Inflammasome in Crescentic Glomerulonephritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Kazuki Kobayashi,
  • Taihei Suzuki,
  • Yuki Kajio,
  • Masataka Ueda,
  • Mayuko Orikasa,
  • Shiho Tamura,
  • Nobuhiro Kanazawa,
  • Masayuki Iyoda,
  • Hirokazu Honda

摘要

Crescentic glomerulonephritis (CrGN) is a severe histological phenotype of immune mediated kidney disease. Although NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation has been implicated in CrGN, its involvement in human glomerular components remains unclear. We reanalyzed publicly available glomerular microarray data from patients with glomerular diseases. We also integrated the mixture matrix from this microarray data with the signature matrix from single nucleus RNA sequencing data using BayesPrism-based deconvolution. NLRP3 inflammasome pathway activity was assessed by gene set variation analysis and validated by immunostaining for NLRP3 using human kidney biopsy specimens. Furthermore, we conducted in vivo experiments using a rat CrGN model treated with shikonin known as an NLRP3 inflammasome inhibitor. NLRP3 inflammasome pathway activation was most prominent in anti-neutrophil cytoplasmic antibody-associated vasculitis. Deconvolution analysis demonstrated increased NLRP3 inflammasome pathway activity across podocytes, parietal epithelial cells (PECs), endothelial cells, and mesangial cells. Human kidney biopsy specimens confirmed increased NLRP3 expression in podocytes and PECs. In the rat CrGN model, shikonin reduced proteinuria, serum creatinine, crescent formation, and podocyte injury, accompanied by decreased expression of NLRP3 inflammasome related genes, and reduced NLRP3 protein expression in podocytes and parietal epithelial cells. NLRP3 inflammasome activation in glomerular resident cells may contribute to AAV-associated CrGN pathogenesis, and pharmacological modulation of this pathway could represent a therapeutic strategy for CrGN.