Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis

Abstract

We have examined the pathogenic role of increased complement expression and activation during kidney fibrosis. Here, we show that PDGFRβ-positive pericytes isolated from mice subjected to obstructive or folic acid injury secrete C1q. This was associated with increased production of proinflammatory cytokines, extracellular matrix components, collagens, and increased Wnt3a-mediated activation of Wnt/β-catenin signaling, which are hallmarks of myofibroblast activation. Real-time PCR, immunoblots, immunohistochemistry, and flow cytometry analysis performed in whole kidney tissue confirmed increased expression of C1q, C1r, and C1s as well as complement activation, which is measured as increased synthesis of C3 fragments predominantly in the interstitial compartment. Flow studies localized increased C1q expression to PDGFRβ-positive pericytes as well as to CD45-positive cells. Although deletion of C1qA did not prevent kidney fibrosis, global deletion of C3 reduced macrophage infiltration, reduced synthesis of C3 fragments, and reduced fibrosis. Clodronate mediated depletion of CD11bF4/80 high macrophages in UUO mice also reduced complement gene expression and reduced fibrosis. Our studies demonstrate local synthesis of complement by both PDGFRβ-positive pericytes and CD45-positive cells in kidney fibrosis. Inhibition of complement activation represents a novel therapeutic target to ameliorate fibrosis and progression of chronic kidney disease.

Screening of genes involved in epithelial‐mesenchymal transition and differential expression of complement‐related genes induced by PAX2 in renal tubules

“…found PDGFRβ‐positive pericytes and CD45‐positive cells could secrete complement components to initiate renal fibrosis. These findings are consistent with our observation that PAX2 may regulate the expression of C3, CD55, and CFH in renal tubular epithelial cells. in vivo experiments will be necessary to further confirm the role of PAX2 in renal tubular epithelial cells.…”

C1q: A fresh look upon an old molecule

“…In addition, while plasma containing circulating C1q as part of C1 complex (Ziccardi and Tschopp, 1982) may represent a possible source of tissue-bound C1q in cases of breached vasculature, it is increasing evident that C1q can be synthesized and secreted locally by various cell types, including macrophages, dendritic cells, fibroblasts, and mast cells that are ubiquitously distributed throughout the body (Ghebrehiwet et al, 2012). In addition, other cells selectively localized in specific tissues and organs such as microglial cells, glomerular and tubular cells, osteoclasts, and trophoblasts contribute to local production of C1q (Fonseca et al, 2017; Xavier et al, 2017). Although C1q is likely to be secreted in limited amount at the extravascular sites, recent evidence suggests that locally synthesized C1q is involved in the regulation of multiple cellular functions in addition to the cellular control of innate and adaptive immunity, as described above.…”

Myocardial Telocyte-Like Cells: A Review Including New Evidence

“…Some of the markers considered useful for the detection of TCs (e.g., vimentin, PDGFRα, and PDGFRβ) are also expressed in pericytes (Table 2) [Witmer et al, 2004;Nees et al, 2013;van Dijk et al, 2015;Chen et al, 2016;Xavier et al, 2017], which are cardiac-resident cells. CD34 and vimentin are commonly expressed in ECs.…”