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Am J Physiol Renal Physiol. 2017 Mar 1;312(3):F516-F532. doi: 10.1152/ajprenal.00604.2016. Epub 2017 Jan 4.

Pericytes and immune cells contribute to complement activation in tubulointerstitial fibrosis.

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Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia.
Department of Cell Biology, University of Virginia, Charlottesville, Virginia.
Department of Biochemistry, University of Virginia, Charlottesville, Virginia.
University of Arkansas for Medical Sciences, Little Rock, Arkansas.
Sanford Burnham Prebys Medical Discovery Institute, Tumor Metastasis and Cancer Immunology Program, La Jolla, California.
Research and Development, Biogen Idec, Cambridge, Massachusetts.
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia;
Salem Veterans Affairs Medical Center, Salem, Virginia.


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.


C1q; C3; pericytes

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