Key Points ADAMTS5 is upregulated in human IgA nephropathy lesions. ADAMTS5 is related to inflammatory infiltrates in affected kidneys. ADAMTS5 digests kidney matrix proteins and cleaves complement C3 and fibronectin. In IgA nephropathy (IgAN), IgA immune complexes are deposited in the mesangium and drive inflammation and extracellular matrix (ECM) remodelling. The functional links between IgA deposition, inflammation, and matrix remodelling are not well characterized. We recently performed urine liquid chromatography–tandem mass spectrometry proteomics and identified multiple ECM glycoproteins whose expression and function in IgAN is unclear. None of the urine glycoproteins was regulated in IgAN transcriptomics, indicating that tissue remodelling rather than increased expression might contribute to their presence in urine. To investigate this, we examined the IgAN expression profile of metalloproteinases, enzymes involved in the remodelling of ECM proteins, and noted that the proteoglycanase ADAMTS5 was upregulated in IgAN kidneys. ADAMTS5 accumulated in areas of inflammation, and ADAMTS5+ cells were seen in the tubulointerstitium and glomeruli. The enzyme was expressed by CD64+ cells and its expression was increased by IL-1 and LPS. Analysis of myeloid cell transcriptomics revealed that ADAMTS5 is enriched in human classical monocytes. ADAMTS5+ cells were present in areas of matrix remodelling and associated with ECM proteins lumican, versican, and collagen-4. Liquid chromatography–tandem mass spectrometry proteomics of kidney explants digested with ADAMTS5, identified multiple kidney proteins affected by ADAMTS5 and revealed specific proteolysis of complement C3 and fibronectin associated with IgA on immune complexes. ADAMTS5 processing of immune complex proteins reduced binding to cultured mesangial cells. ADAMTS5 is associated with interstitial inflammatory cells in IgAN and other kidney lesions and fragments relevant extracellular proteins. The proteolytic enzyme might be a new translational target relevant to inflammation and scarring in kidney disease.

中文翻译：

---

金属蛋白酶 ADAMTS5 在 IgA 肾病中由间质炎症细胞表达，并在肾基质上具有蛋白水解活性

要点 ADAMTS5 在人 IgA 肾病病变中上调。ADAMTS5 与受累肾脏的炎症浸润有关。ADAMTS5 消化肾脏基质蛋白并裂解补体 C3 和纤连蛋白。在 IgA 肾病 (IgAN) 中，IgA 免疫复合物沉积在系膜中并驱动炎症和细胞外基质 (ECM) 重塑。IgA 沉积、炎症和基质重塑之间的功能联系尚未得到很好的表征。我们最近进行了尿液液相色谱-串联质谱蛋白质组学，并鉴定了多种 ECM 糖蛋白，其在 IgAN 中的表达和功能尚不清楚。在 IgAN 转录组学中，没有一种尿糖蛋白受到调节，这表明组织重塑而不是表达增加可能有助于它们在尿液中的存在。为了调查这件事，我们检查了金属蛋白酶（参与 ECM 蛋白重塑的酶）的 IgAN 表达谱，并注意到蛋白聚糖酶 ADAMTS5 在 IgAN 肾脏中上调。ADAMTS5 在炎症区域积累，在肾小管间质和肾小球中可见 ADAMTS5+ 细胞。该酶由 CD64+ 细胞表达，IL-1 和 LPS 增加其表达。骨髓细胞转录组学分析显示 ADAMTS5 富含人类经典单核细胞。ADAMTS5+ 细胞存在于基质重塑区域，并与 ECM 蛋白 lumican、versican 和胶原蛋白 4 相关。ADAMTS5消化的肾外植体的液相色谱-串联质谱蛋白质组学，鉴定了多种受 ADAMTS5 影响的肾脏蛋白质，并揭示了补体 C3 和与免疫复合物上 IgA 相关的纤连蛋白的特异性蛋白水解。ADAMTS5 对免疫复合物蛋白的处理降低了与培养的系膜细胞的结合。ADAMTS5 与 IgAN 和其他肾脏病变中的间质炎症细胞和相关细胞外蛋白片段相关。蛋白水解酶可能是与肾脏疾病中的炎症和瘢痕形成相关的新转化靶标。