A previously unrecognized role of C3a in proteinuric progressive nephropathy

Marina Morigi, Monica Locatelli, Cinzia Rota, Simona Buelli, Daniela Corna, Paola Rizzo, Mauro Abbate, Debora Conti, Luca Perico, Lorena Longaretti, Ariela Benigni, Carlamaria Zoja, Giuseppe Remuzzi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number28445
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Jun 27 2016

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Podocytes
Glial Cell Line-Derived Neurotrophic Factor
Epithelial Cells
Bovine Serum Albumin
Alternative Complement Pathway
Complement Factor B
Up-Regulation
Complement C3a
Complement Factor H
Complement C3
Cell Movement
Proteins
Wounds and Injuries

ASJC Scopus subject areas

  • General

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A previously unrecognized role of C3a in proteinuric progressive nephropathy. / Morigi, Marina; Locatelli, Monica; Rota, Cinzia; Buelli, Simona; Corna, Daniela; Rizzo, Paola; Abbate, Mauro; Conti, Debora; Perico, Luca; Longaretti, Lorena; Benigni, Ariela; Zoja, Carlamaria; Remuzzi, Giuseppe.

In: Scientific Reports, Vol. 6, 28445, 27.06.2016.

Research output: Contribution to journalArticle

Morigi, Marina ; Locatelli, Monica ; Rota, Cinzia ; Buelli, Simona ; Corna, Daniela ; Rizzo, Paola ; Abbate, Mauro ; Conti, Debora ; Perico, Luca ; Longaretti, Lorena ; Benigni, Ariela ; Zoja, Carlamaria ; Remuzzi, Giuseppe. / A previously unrecognized role of C3a in proteinuric progressive nephropathy. In: Scientific Reports. 2016 ; Vol. 6.
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