Role of intracellular complement activation in kidney fibrosis

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.

Automated summary

Increased expression of complement C1r, C1s and C3 in kidney cells plays a crucial role in kidney fibrosis, with activation occurring through both classical and alternative pathways. Studies in mice with unilateral ureteral obstruction reveal enhanced synthesis of complement C3 and C5 in renal tubular epithelial cells, along with increased expression of complement receptors C3ar1 and C5ar1 in interstitial cells, indicating compartmentalization of complement components during kidney injury. Global deletion of C3 and macrophage ablation can prevent inflammation and reduce kidney scarring, but further insights into the mechanisms of intracellular complement activation leading to fibrosis and progressive kidney disease could be gained from cell-specific deletion of complement components and regulators in mice.