Department of Medicine and Center for Immunity and Regenerative Medicine, University of Virginia, Charlottesville, Virginia, USA.
Br J Pharmacol. 2021 Jul;178(14):2880-2891. doi: 10.1111/bph.15408. Epub 2021 Feb 27.
Increased expression of complement C1r, C1s and C3 in kidney cells plays an important role in the pathogenesis of kidney fibrosis. Our studies suggest that activation of complement in kidney cells with increased generation of C3 and its fragments occurs by activation of classical and alternative pathways. Single nuclei RNA sequencing studies in kidney tissue from unilateral ureteral obstruction mice show that increased synthesis of complement C3 and C5 occurs primarily in renal tubular epithelial cells (proximal and distal), while increased expression of complement receptors C3ar1 and C5ar1 occurs in interstitial cells including immune cells like monocytes/macrophages suggesting compartmentalization of complement components during kidney injury. Although global deletion of C3 and macrophage ablation prevent inflammation and reduced kidney tissue scarring, the development of mice with cell-specific deletion of complement components and their regulators could bring further insights into the mechanisms by which intracellular complement activation leads to fibrosis and progressive kidney disease. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
补体 C1r、C1s 和 C3 在肾细胞中的表达增加在肾纤维化的发病机制中起着重要作用。我们的研究表明，补体在细胞中的激活，导致 C3 及其片段的生成增加，是通过经典途径和替代途径的激活发生的。单侧输尿管梗阻小鼠肾组织的单细胞 RNA 测序研究表明，补体 C3 和 C5 的合成增加主要发生在肾小管上皮细胞（近端和远端），而补体受体 C3ar1 和 C5ar1 的表达增加发生在包括单核细胞/巨噬细胞在内的间质细胞中，提示补体成分在肾损伤过程中的区室化。尽管 C3 的全局缺失和巨噬细胞消融可预防炎症和减少肾组织瘢痕形成，但细胞特异性缺失补体成分及其调节剂的小鼠的发展可能会进一步深入了解细胞内补体激活导致纤维化和进行性肾病的机制。相关文章：本文是补体系统在健康和疾病中的经典和非经典功能专题的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
