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Complement C1r serine protease contributes to kidney fibrosis.

We reported that complement activation precedes the development of kidney fibrosis, however, little is known about the cellular mechanisms involved in this transition. We hypothesize 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 the expression of C1r in untreated wild type (WT) mice is higher in liver when compared to 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 studies 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 when compared to WT mice. C1r deletion reduced expression of C1s, C3 fragments 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 acute phase response, complement, proliferation of connective tissue cells (e.g. PDGFRβ), and reduced expression of genes associated with inflammation when compared to FA-treated WT mice. In vitro studies in renal epithelial cells demonstrated that C1s expression is dependent on increased C1r expression, and that interferon gamma induces the expression of these two proteases. We conclude that increased expression of C1 complex proteases is associated with increased tissue inflammation, complement C3 formation, and represents an important pathogenic mechanism leading to FA-mediated tubulointerstitial fibrosis.