title: 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.
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Ranjit K
authors.initials: RK
authors.lastname: Sahu
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Landes
authors.affiliation: Department of Cell Biology, University of Virginia, Charlottesville, Virginia.
authors.forename: Jing
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, University of Virginia, Charlottesville, Virginia.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Taylor
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Srinivas
authors.initials: S
authors.lastname: Ayyadevara
authors.affiliation: University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Judit
authors.initials: J
authors.lastname: Megyesi
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, Tumor Metastasis and Cancer Immunology Program, La Jolla, California.
authors.forename: William B
authors.initials: WB
authors.lastname: Stallcup
authors.affiliation: Research and Development, Biogen Idec, Cambridge, Massachusetts.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: Edimara S
authors.initials: ES
authors.lastname: Reis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, Virginia; dp2bs@virginia.edu.|Salem Veterans Affairs Medical Center, Salem, Virginia.
authors.forename: Didier
authors.initials: D
authors.lastname: Portilla
mesh_terms: D000818:Animals; D002450:Cell Communication; D003167:Complement Activation; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005355:Fibrosis; D005492:Folic Acid; D005838:Genotype; D018836:Inflammation Mediators / Q000378:metabolism; D007684:Kidney Tubules / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020286:Pericytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014517:Ureteral Obstruction / Q000150:complications; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism
chemical_list: C545610:C3 protein, mouse; D003176:Complement C3; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D018836:Inflammation Mediators; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D015922:Complement C1q; D005492:Folic Acid; D020797:Receptor, Platelet-Derived Growth Factor beta; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse
keywords: C1q; C3; pericytes