Complement C1r serine protease contributes to kidney fibrosis.

Abstract

We have previously reported that complement activation precedes the development of kidney fibrosis; however, little is known about the cellular mechanisms involved in this transition. We hypothesized that increased expression of C1 complex protease C1r, the initiator of complement activation, contributes to tubulointerstitial fibrosis and tested this idea in mice with global deletion of C1r. Although expression of C1r in untreated wild-type (WT) mice was higher in the liver compared with kidney tissue, administration of folic acid (FA) led to upregulation of C1r mRNA and protein levels only in kidney tissue. Immunohistochemistry and in situ hybridization experiments localized increased expression of C1r and C1s proteases to renal tubular epithelial cells. C1r-null mice had reduced acute tubular injury and inflammation measured 2 days after FA administration compared with WT mice. C1r deletion reduced expression of C1s, C3 fragment formation, and organ fibrosis measured 14 days after FA administration. Differential gene expression performed in kidney tissue demonstrated that C1r-null mice had reduced expression of genes associated with the acute phase response, complement, proliferation of connective tissue cells (e.g., platelet-derived growth factor receptor-β), and reduced expression of genes associated with inflammation compared with FA-treated WT mice. In vitro experiments in renal epithelial cells demonstrated that C1s expression is dependent on increased C1r expression and that interferon-γ induces the expression of these two proteases. We conclude that increased expression of C1 complex proteases is associated with increased tissue inflammation and complement C3 formation and represents an important pathogenic mechanism leading to FA-mediated tubulointerstitial fibrosis.

• Authors: Sandhya Xavier, Ranjit K Sahu, Sai Vineela Bontha, Valeria Mass, Ronald P Taylor, Judit Megyesi, Nicole M Thielens, Didier Portilla
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 317 Issue 5 Pg. F1293-F1304 (11 01 2019) ISSN: 1522-1466 [Electronic] United States
• PMID: 31509012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• RNA, Messenger
• Folic Acid
• Complement C1r
• Complement C1s

Topics

• Animals
• Cell Line
• Complement C1r (genetics, metabolism)
• Complement C1s (genetics, metabolism)
• Epithelial Cells (drug effects, metabolism)
• Folic Acid (pharmacology)
• Gene Expression Regulation, Enzymologic
• Humans
• Inflammation
• Kidney (cytology)
• Kidney Diseases (enzymology, genetics)
• Male
• Mice
• Mice, Knockout
• RNA, Messenger (genetics, metabolism)