title: A previously unrecognized role of C3a in proteinuric progressive nephropathy.
abstract: Podocyte loss is the initial event in the development of glomerulosclerosis, the structural hallmark of progressive proteinuric nephropathies. Understanding mechanisms underlying glomerular injury is the key challenge for identifying novel therapeutic targets. In mice with protein-overload induced by bovine serum albumin (BSA), we evaluated whether the alternative pathway (AP) of complement mediated podocyte depletion and podocyte-dependent parietal epithelial cell (PEC) activation causing glomerulosclerosis. Factor H (Cfh(-/-)) or factor B-deficient mice were studied in comparison with wild-type (WT) littermates. WT+BSA mice showed podocyte depletion accompanied by glomerular complement C3 and C3a deposits, PEC migration to capillary tuft, proliferation, and glomerulosclerosis. These changes were more prominent in Cfh(-/-) +BSA mice. The pathogenic role of AP was documented by data that factor B deficiency preserved glomerular integrity. In protein-overload mice, PEC dysregulation was associated with upregulation of CXCR4 and GDNF/c-Ret axis. In vitro studies provided additional evidence of a direct action of C3a on proliferation and CXCR4-related migration of PECs. These effects were enhanced by podocyte-derived GDNF. In patients with proteinuric nephropathy, glomerular C3/C3a paralleled PEC activation, CXCR4 and GDNF upregulation. These results indicate that mechanistically uncontrolled AP complement activation is not dispensable for podocyte-dependent PEC activation resulting in glomerulosclerosis.
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Locatelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rota
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Buelli
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Abbate
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Conti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Perico
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Carlamaria
authors.initials: C
authors.lastname: Zoja
authors.affiliation: IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.|Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale (ASST) Papa Giovanni XXIII, Bergamo, Italy.|Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000328:Adult; D000818:Animals; D002417:Cattle; D049109:Cell Proliferation; D002478:Cells, Cultured; D015926:Complement C3a / Q000378:metabolism*; D011415:Complement Factor B / Q000172:deficiency / Q000235:genetics; D017242:Complement Factor H / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D050199:Podocytes / Q000166:cytology / Q000378:metabolism; D011507:Proteinuria / Q000209:etiology; D012710:Serum Albumin, Bovine / Q000008:administration & dosage; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D012710:Serum Albumin, Bovine; D015926:Complement C3a; D017242:Complement Factor H; D011415:Complement Factor B